Variant rs515726204 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_031448.6(C19orf12):c.171_181del(p.Gly58ArgfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000812 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

C19orf12
NM_031448.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 7.26

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-29702956-AACAGCCCCCCG-A is Pathogenic according to our data. Variant chr19-29702956-AACAGCCCCCCG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C19orf12	NM_031448.6 linkuse as main transcript	c.171_181del	p.Gly58ArgfsTer10	frameshift_variant	3/3	ENST00000323670.14	NP_113636.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C19orf12	ENST00000323670.14 linkuse as main transcript	c.171_181del	p.Gly58ArgfsTer10	frameshift_variant	3/3	2	NM_031448.6	ENSP00000313332	P1	Q9NSK7-4

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000762

AC:

AN:

249194

Hom.:

AF XY:

0.0000890

AC XY:

AN XY:

134876

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000152

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000807

AC:

118

AN:

1461870

Hom.:

AF XY:

0.0000798

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.0000989

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000486

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2021	Frameshift variant predicted to result in protein truncation, as the last 84 amino acids are replaced with 9 different amino acids; This variant is associated with the following publications: (PMID: 23269600, 28347614, 23494994, 24636776, 23436634, 21981780) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	- -

Hereditary spastic paraplegia 43

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Gly69Argfs*10) in the C19orf12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 84 amino acid(s) of the C19orf12 protein. This variant is present in population databases (rs515726204, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with autosomal recessive neurodegeneration with brain iron accumulation or mitochondria protein-associated neurodegeneration (PMID: 21981780, 23436634, 28641177, 30392167). It is commonly reported in individuals of Polish ancestry (PMID: 21981780, 23436634, 28641177, 30392167). ClinVar contains an entry for this variant (Variation ID: 31155). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported to be associated with C19orf12 related disorder (ClinVar ID: VCV000031155, PMID:21981780).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000100, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Neurodegeneration with brain iron accumulation 4

Pathogenic:1Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 15, 2013	- -
not provided, no classification provided	literature only	GeneReviews	-	Founder variant in Eastern European (Polish) population; Associated with juvenile onset -

C19orf12-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2024

The C19orf12 c.204_214del11 variant is predicted to result in a frameshift and premature protein termination (p.Gly69Argfs*10). This variant has primarily been reported in the homozygous or compound heterozygous states in individuals with autosomal recessive neurodegeneration with brain iron accumulation (see for example, Table 1, Hartig et al. 2011. PubMed ID: 21981780; Table 1, Schulte et al. 2012. PubMed ID: 23436634; Goldman et al. 2013. PubMed ID: 23494994). In these studies heterozygous carriers were reported as unaffected. However, in a single case it has also been associated with autosomal dominant neurodegeneration with brain iron accumulation (Table 1, Sparber et al. 2021. PubMed ID: 33607528). This variant has been classified as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/31155/). Given the evidence, we interpret this variant as pathogenic in the context of autosomal recessive disease, and as a variant of uncertain significance in the context of autosomal dominant disease. -

Neurodegeneration with brain iron accumulation

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 29, 2023

Variant summary: C19orf12 c.171_181del11/p.Gly58ArgfsX10 (legacy name c.204_214del11/p.Gly69ArgfsX10) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with Neurodegeneration With Brain Iron Accumulation in HGMD. The variant allele was found at a frequency of 7.6e-05 in 249194 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in C19orf12 causing Neurodegeneration With Brain Iron Accumulation (7.6e-05 vs 0.0006). c.171_181del11 has been reported in the literature in multiple individuals affected with Neurodegeneration With Brain Iron Accumulation (Gregory_2019, Sparber_2021, etc). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic (n=3) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over