rs515726204

Variant names:

• chr19-29702956-AACAGCCCCCCG-A
• rs515726204
• NM_031448.6:c.171_181delCGGGGGGCTGT

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_031448.6(C19orf12):​c.171_181delCGGGGGGCTGT​(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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 7.26

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]

ACMG classification

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 rank	MANE	Protein	UniProt
C19orf12	NM_031448.6	c.171_181delCGGGGGGCTGT	p.Gly58ArgfsTer10	frameshift_variant	Exon 3 of 3	ENST00000323670.14	NP_113636.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C19orf12	ENST00000323670.14	c.171_181delCGGGGGGCTGT	p.Gly58ArgfsTer10	frameshift_variant	Exon 3 of 3	2	NM_031448.6	ENSP00000313332.9

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152134 Hom.: 0 Cov.: 32

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: 19 AN: 249194 Hom.: 0 AF XY: 0.0000890 AC XY: 12 AN XY: 134876

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.: 0 AF XY: 0.0000798 AC XY: 58 AN XY: 727240

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: 13 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74324

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.: 0

Bravo AF: 0.0000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Nov 30, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurodegeneration with brain iron accumulation 4 Pathogenic:2 Other:1

Jan 15, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodegeneration with brain iron accumulation 4 (MIM#614298). A dominant negative mechanism has been suggested to cause autosomal dominant disease (PMID: 31087512). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance has been reported for the majority of premature termination variants located in exon 3 (PMID: 31087512). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.0 (28 heterozygotes, 0 homozygotes). (SP) 0701 - Other truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar. This variant has also been observed in multiple homozygous or compound heterozygous individuals with neurodegeneration with brain iron accumulation (PMID: 21981780). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Founder variant in Eastern European (Polish) population; Associated with juvenile onset -

Hereditary spastic paraplegia 43 Pathogenic:2

Jan 03, 2022

3billion, Medical Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

C19orf12-related disorder Pathogenic:1

May 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Mar 29, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Mar 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs515726204; hg19: chr19-30193863;