chr19-29702725-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PM1PP2PP3BP6_Very_StrongBS1BS2

The NM_031448.6(C19orf12):c.413A>G(p.Gln138Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 1,613,840 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q138K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0025 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 11 hom. )

Consequence

C19orf12
NM_031448.6 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.781

Publications

8 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: Benign. The variant received -12 ACMG points.

PM1

In a chain Protein C19orf12 (size 151) in uniprot entity CS012_HUMAN there are 10 pathogenic changes around while only 4 benign (71%) 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

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 19-29702725-T-C is Benign according to our data. Variant chr19-29702725-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 380881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00254 (387/152298) while in subpopulation NFE AF = 0.00471 (320/68006). AF 95% confidence interval is 0.00428. There are 2 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,SD,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C19orf12	NM_031448.6 link	c.413A>G	p.Gln138Arg	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.413A>G	p.Gln138Arg	missense_variant	Exon 3 of 3	2	NM_031448.6	ENSP00000313332.9		Q9NSK7-4

Frequencies

GnomAD3 genomes

AF:

0.00255

AC:

388

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00472

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00231

AC:

579

AN:

250284

AF XY:

0.00225

show subpopulations

Gnomad AFR exome

AF:

0.000573

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00449

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.00344

AC:

5025

AN:

1461542

Hom.:

Cov.:

AF XY:

0.00325

AC XY:

2362

AN XY:

727072

show subpopulations

African (AFR)

AF:

0.000597

AC:

AN:

33478

American (AMR)

AF:

0.000425

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000209

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00190

AC:

101

AN:

53154

Middle Eastern (MID)

AF:

0.000525

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00423

AC:

4703

AN:

1112006

Other (OTH)

AF:

0.00263

AC:

159

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

335

670

1006

1341

1676

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

368

552

736

920

<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:

0.00254

AC:

387

AN:

152298

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

148

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41572

American (AMR)

AF:

0.000588

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00471

AC:

320

AN:

68006

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00325

Hom.:

Bravo

AF:

0.00224

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00273

AC:

331

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00316

EpiControl

AF:

0.00302

ClinVar

Significance: Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27112773) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

C19orf12: PP3, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 43

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neurodegeneration with brain iron accumulation 4

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary spastic paraplegia

Benign:1

Aug 24, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

6.5

(source)

DANN

Benign

0.48

DEOGEN2

Benign

0.0075

.;.;.;.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.58

T;T;.;.;T

M_CAP

Benign

0.070

MetaRNN

Benign

0.0061

T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.10

.;.;.;.;N

PhyloP100

-0.78

PROVEAN

Benign

-0.080

.;.;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.63

.;.;T;T;T

Sift4G

Benign

0.53

T;T;T;T;T

Vest4

0.0060

MVP

0.21

MPC

0.37

ClinPred

0.0011

GERP RS

-4.1

Varity_R

0.027

gMVP

0.27

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.69

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.69

Position offset: 0

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over