rs121434325

Positions:

• chr5-60904794-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_000082.4(ERCC8):​c.479C>T​(p.Ala160Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000948 in 1,582,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A160T) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0000098 (0 hom.)
• Consequence: ERCC8 NM_000082.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1 O:1
• Conservation: PhyloP100: 8.33

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]

ERCC8 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-60904795-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769
• PP5: Variant 5-60904794-G-A is Pathogenic according to our data. Variant chr5-60904794-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-60904794-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC8	NM_000082.4	c.479C>T	p.Ala160Val	missense_variant, splice_region_variant	5/12	ENST00000676185.1	NP_000073.1
ERCC8	NM_001007233.3	c.305C>T	p.Ala102Val	missense_variant, splice_region_variant	6/13		NP_001007234.1
ERCC8	NM_001007234.3	c.479C>T	p.Ala160Val	missense_variant, splice_region_variant	5/6		NP_001007235.1
ERCC8	NM_001290285.2	c.23-1078C>T		intron_variant			NP_001277214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC8	ENST00000676185.1	c.479C>T	p.Ala160Val	missense_variant, splice_region_variant	5/12		NM_000082.4	ENSP00000501614.1

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150466 Hom.: 0 Cov.: 26

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250708 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135526

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: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000978 AC: 14 AN: 1431894 Hom.: 0 Cov.: 25 AF XY: 0.00000980 AC XY: 7 AN XY: 714194

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: 0.00

Gnomad4 NFE exome AF: 0.0000129

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150466 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 73346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000722 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 12, 2022	PP3, PP4, PM2, PM3, PM5, PS4_moderate -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2021	Identified in the presence of a second ERCC8 variant, phase unknown, in a patient with Cockayne syndrome (Ridley et al., 2005).; Published studies demonstrate a damaging effect; specifically, this variant causes the deletion of exon 5 in the transcipt (Nardo et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29742419, 19329487, 15744458, 29572252, 33199595) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 02, 2023	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 160 of the ERCC8 protein (p.Ala160Val). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs121434325, gnomAD 0.002%). This missense change has been observed in individual(s) with Cockayne syndrome type A (PMID: 15744458, 29572252). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1717). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change results in deletion of exon 5 and introduces a premature termination codon (PMID: 15744458). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Cockayne syndrome type 1 Pathogenic:1 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Counsyl	Oct 25, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2005	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.19	T;.
Polyphen		1.0	D;.
Vest4		0.89
MutPred		0.39		Loss of ubiquitination at K155 (P = 0.1264);.;
MVP		0.90
MPC		0.28
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.81
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.35		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434325; hg19: chr5-60200621;