rs121434324

Variant names:

• chr5-60944972-C-A
• rs121434324
• NM_000082.4:c.37G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-60944972-C-A
• chr5-60944972-C-G
• chr5-60944972-C-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000082.4(ERCC8):​c.37G>T​(p.Glu13*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: ERCC8 NM_000082.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.45
• Publications: 7 publications found

Genes affected

ERCC8 (HGNC:3439): (ERCC excision repair 8, CSA ubiquitin ligase complex subunit) This gene encodes a WD repeat protein, which interacts with Cockayne syndrome type B (CSB) protein and with p44 protein, a subunit of the RNA polymerase II transcription factor IIH. Mutations in this gene have been identified in patients with hereditary disease Cockayne syndrome (CS). CS cells are abnormally sensitive to ultraviolet radiation and are defective in the repair of transcriptionally active genes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]

NDUFAF2 (HGNC:28086): (NADH:ubiquinone oxidoreductase complex assembly factor 2) NADH:ubiquinone oxidoreductase (complex I) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. This gene encodes a complex I assembly factor. Mutations in this gene cause progressive encephalopathy resulting from mitochondrial complex I deficiency. [provided by RefSeq, Jul 2008]

NDUFAF2 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P
• mitochondrial complex I deficiency, nuclear type 10

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 91 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-60944972-C-A is Pathogenic according to our data. Variant chr5-60944972-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1716.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
ERCC8	NM_000082.4	c.37G>T	p.Glu13*	stop_gained	Exon 1 of 12	ENST00000676185.1	NP_000073.1
NDUFAF2	NM_174889.5	c.-284C>A		upstream_gene_variant		ENST00000296597.10	NP_777549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC8	ENST00000676185.1	c.37G>T	p.Glu13*	stop_gained	Exon 1 of 12		NM_000082.4	ENSP00000501614.1
NDUFAF2	ENST00000296597.10	c.-284C>A		upstream_gene_variant		1	NM_174889.5	ENSP00000296597.5

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152150 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000755 AC: 19 AN: 251494 AF XY: 0.0000809

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000458 AC: 67 AN: 1461866 Hom.: 0 Cov.: 30 AF XY: 0.0000550 AC XY: 40 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111986

Other (OTH) AF: 0.0000993 AC: 6 AN: 60396

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152150 Hom.: 0 Cov.: 30 AF XY: 0.0000404 AC XY: 3 AN XY: 74342

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000195 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Jan 20, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25333069, 29572252, 29742419, 14661080, 15744458, 19894250) -

Mar 30, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2024

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.Glu13*) in the ERCC8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC8 are known to be pathogenic (PMID: 29572252). This variant is present in population databases (rs121434324, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with Cockayne syndrome (PMID: 14661080, 29572252). ClinVar contains an entry for this variant (Variation ID: 1716). For these reasons, this variant has been classified as Pathogenic. -

Cockayne syndrome type 1 Pathogenic:3

Jan 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 06, 2020

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000082.3(ERCC8):c.37G>T(E13*) is classified as pathogenic in the context of ERCC8-related disorders. Sources cited for classification include the following: PMID 19894250 and 14661080. Classification of NM_000082.3(ERCC8):c.37G>T(E13*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

Jul 03, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu13X variant in ERCC8 has been reported in 2 compound heterozygous and 3 homozgyous individuals with Cockayne syndrome (Cao 2004 PMID:14661080, Laugel 2010 PMID: 19894250, Calmels 2018 PMID: 29572252). It has been identified in 0.139% (14/10080) of Ashkenazi Jewish chromosomes and 0.004% of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). It is also reported in ClinVar (Variation ID: 1716). This nonsense variant leads to a premature termination codon at position 13, which is predicted to lead to a truncated or absent protein. Loss of function of the ERCC8 gene is an established disease mechanism in autosomal recessive Cockayne syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Cockayne syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong. -

Cockayne syndrome type 1;C3553298:UV-sensitive syndrome 2 Pathogenic:1

May 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cockayne syndrome Pathogenic:1

Dec 23, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ERCC8 c.37G>T (p.Glu13X) 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. The variant allele was found at a frequency of 7.6e-05 in 251494 control chromosomes (gnomAD). c.37G>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Cockayne Syndrome (Cao_2004, Ridley_2005, Nardo_2009, Calmels_2018). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated the lack of protein product and greatly decreased cell survival after UV irradiation in patient derived fibroblasts (Ridley_2005, Nardo_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.92	D
PhyloP100		2.4
Vest4		0.67
ClinPred		0.92	D
GERP RS		5.7
PromoterAI		0.0079	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121434324; hg19: chr5-60240799;