chr19-29702923-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PP2PP3_StrongPP5_Very_Strong

The NM_031448.6(C19orf12):c.215C>T(p.Pro72Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P72S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

C19orf12
NM_031448.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.21

Publications

1 publications found

Variant links:

Genes affected

C19orf12 (HGNC:25443): (chromosome 19 open reading frame 12) This gene encodes a small transmembrane protein. Mutations in this gene are a cause of neurodegeneration with brain iron accumulation-4 (NBIA4), but the specific function of the encoded protein is unknown. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

C19orf12 Gene-Disease associations (from GenCC):

neurodegeneration with brain iron accumulation 4
Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Illumina, Ambry Genetics, G2P
hereditary spastic paraplegia 43
Inheritance: AR Classification: LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

C19orf12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PM1

In a chain Protein C19orf12 (size 151) in uniprot entity CS012_HUMAN there are 13 pathogenic changes around while only 4 benign (76%) in NM_031448.6

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Trascript score misZ: 1.0658 (below the threshold of 3.09). GenCC associations: The gene is linked to neurodegeneration with brain iron accumulation 4, hereditary spastic paraplegia 43.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

PP5

Variant 19-29702923-G-A is Pathogenic according to our data. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702923-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 225875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C19orf12	NM_031448.6 link	c.215C>T	p.Pro72Leu	missense_variant	Exon 3 of 3	ENST00000323670.14	NP_113636.2	Q9NSK7-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C19orf12	ENST00000323670.14 link	c.215C>T	p.Pro72Leu	missense_variant	Exon 3 of 3	2	NM_031448.6	ENSP00000313332.9		Q9NSK7-4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000200

AC:

AN:

249460

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000358

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1112008

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000547

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurodegeneration with brain iron accumulation 4

Pathogenic:3

Sep 01, 2022

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.74). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 26187298). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 26187298). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 15, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

.;.;.;.;.;T;T

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;.;.;D;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

3.2

.;.;.;.;.;M;.

PhyloP100

9.2

PROVEAN

Pathogenic

-9.3

.;.;D;D;.;D;.

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0010

.;.;D;D;.;D;.

Sift4G

Uncertain

0.0030

D;D;D;D;D;D;.

Vest4

0.70

MVP

0.60

MPC

1.1

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.72

gMVP

0.82

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over