dbSNP rs515726205: C19orf12:p.Gly58Arg (chr19-29702966-C-T) – ACMG Classification: Pathogenic (17 pts)

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3PM1PP2PP3_ModeratePP5_Very_Strong

The NM_031448.6(C19orf12):c.172G>A(p.Gly58Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,708 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 (★★). ClinVar reports functional evidence for this variant: "SCV000967601: In vitro functional studies support an impact to protein function (Landoure 2013)" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G58G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

C19orf12
NM_031448.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.26

Publications

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

C19orf12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000967601: In vitro functional studies support an impact to protein function (Landoure 2013); SCV000647089: Experimental studies have shown that this missense change affects C19orf12 function (PMID: 23857908).

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain 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, 0.851

PP5

Variant 19-29702966-C-T is Pathogenic according to our data. Variant chr19-29702966-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 31157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031448.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C19orf12	NM_031448.6	MANE Select	c.172G>A	p.Gly58Arg	missense	Exon 3 of 3	NP_113636.2	Q9NSK7-4
C19orf12	NM_001031726.4		c.172G>A	p.Gly58Arg	missense	Exon 3 of 3	NP_001026896.3	Q9NSK7-4
C19orf12	NM_001256047.2		c.172G>A	p.Gly58Arg	missense	Exon 3 of 3	NP_001242976.1	Q9NSK7-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C19orf12	ENST00000323670.14	TSL:2 MANE Select	c.172G>A	p.Gly58Arg	missense	Exon 3 of 3	ENSP00000313332.9	Q9NSK7-4
C19orf12	ENST00000592153.5	TSL:1	c.172G>A	p.Gly58Arg	missense	Exon 3 of 4	ENSP00000467117.1	Q9NSK7-3
C19orf12	ENST00000591243.1	TSL:1	c.172G>A	p.Gly58Arg	missense	Exon 2 of 2	ENSP00000467516.1	K7EPS8

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152082

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000241

AC:

AN:

249134

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000538

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461626

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000234

AC:

AN:

1111774

Other (OTH)

AF:

0.0000331

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

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:

0.0000132

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74288

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41430

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000439

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurodegeneration with brain iron accumulation 4 (4)

not provided (2)

Dystonic disorder;C0040822:Tremor;C0234985:Mental deterioration;C0241688:Peripheral visual field loss;C4024790:Adult-onset night blindness (1)

Hereditary spastic paraplegia 43 (1)

Hereditary spastic paraplegia 43;C3280371:Neurodegeneration with brain iron accumulation 4 (1)

Neurodegeneration with brain iron accumulation (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

0.65

MutationAssessor

Pathogenic

2.9

PhyloP100

7.3

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Vest4

0.94

MutPred

0.58

Gain of methylation at G58 (P = 0.0172)

MVP

0.73

MPC

1.1

ClinPred

0.97

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.86

gMVP

0.98

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over