rs281875222

Positions:

• chr5-60904795-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_000082.4(ERCC8):​c.478G>A​(p.Ala160Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000378 in 1,587,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A160V) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: ERCC8 NM_000082.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 O:1
• Conservation: PhyloP100: 6.57

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-60904794-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801
• PP5: Variant 5-60904795-C-T is Pathogenic according to our data. Variant chr5-60904795-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68753.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_pathogenic=2}. Variant chr5-60904795-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC8	NM_000082.4	c.478G>A	p.Ala160Thr	missense_variant	5/12	ENST00000676185.1	NP_000073.1
ERCC8	NM_001007233.3	c.304G>A	p.Ala102Thr	missense_variant	6/13		NP_001007234.1
ERCC8	NM_001007234.3	c.478G>A	p.Ala160Thr	missense_variant	5/6		NP_001007235.1
ERCC8	NM_001290285.2	c.23-1079G>A		intron_variant			NP_001277214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC8	ENST00000676185.1	c.478G>A	p.Ala160Thr	missense_variant	5/12		NM_000082.4	ENSP00000501614.1

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150594 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000663

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000348 AC: 5 AN: 1437276 Hom.: 0 Cov.: 25 AF XY: 0.00000558 AC XY: 4 AN XY: 716542

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000673

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: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150594 Hom.: 0 Cov.: 26 AF XY: 0.0000136 AC XY: 1 AN XY: 73426

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000663

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 10, 2024

Variant summary: GJB2 c.478G>A (p.Gly160Ser) results in a non-conservative amino acid change located in the cysteine-rich domain (IPR019570) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0007 in 1622152 control chromosomes including one homozygote, predominantly at a frequency of 0.0021 within the African or African-American subpopulation in the gnomAD database (v4.0.0). TThis frequency is about 85-fold higher than the estimated maximum for a pathogenic variant in GJB2 causing Autosomal Dominant Non-Syndromic Hearing Loss (NSHL) (0.0022 vs. 2.5E-05), that rules out the dominant inheritance mode for the variant. However, this frequency is not higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive NSHL (0.0022 vs. 0.025), allowing no conclusion about variant significance for the recessive mode of inheritance. Additional evidence supporting the benign nature of this variant comes from a study which identified the variant in 7/7401 North American hearing loss patients (Putcha 2007). This represents a lower allele frequency (0.00047) in the North American hearing loss population, than either the highest observed allele frequency (0.0022) or the overall frequency for diverse ethnicities (0.0006) of the variant in the control cohort (in gnomAD). The variant, c.478G>A, has been reported in the literature in several individuals affected with Non-Syndromic Hearing Loss, however in most of these cases there was no second allele identified, and in some cases the variant was also mentioned to be present in heterozygosity in unaffected family member (e.g. Wu 2002, Janecke 2002, Gasmelseed 2004, Azaiez 2004, Cheng 2005, Tang 2006, Primignani 2009, Ji 2011, Koohiyan_2019, Ozylmaz_2019, Abtahi_2020); therefore these reports do not indicate a pathogenic role for the variant. Though the variant was reported to be found in homozygosity in one patient from an inbred family, no further information (i.e. co-segregation or co-occurrence data) was provided (Khalifa Alkowari 2012). In a few cases the variant was found in compound heterozygosity with a (potentially) pathogenic allele in patients; however, the phase of the variants was not confirmed by parental testing (Snoeckx 2005, Zhang 2011, Yu_2020). Moreover, the variant was also found in a compound heterozygote (V37I/G160S) with normal hearing (Roux 2004), arguing against its pathogenicity. At least two NSHL patients, homozygous for the common disease variant c.235delC, were reported to also carry the variant of interest, indicating the variant to be in the benign spectrum (Jiang 2014, Zheng 2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15070423, 17041943, 15365987, 16380907, 14722929, 17426645, 12172394, 12189487, 22695344, 16222667, 9600457, 19371219, 17666888, 19043807, 22103400, 21162657, 19235794, 21366436, 19125024, 31992338, 15832357, 26043044, 24737404, 30245029, 30466042, 31569309, 31620696). ClinVar contains an entry for this variant (Variation ID: 44755). Based on the evidence outlined above, the variant was classified as likely benign. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 13, 2024

- -

Cockayne syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 10, 2024

Variant summary: ERCC8 c.478G>A (p.Ala160Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250786 control chromosomes. c.478G>A has been reported in the literature as a homozygous genotype in individuals affected with Cockayne Syndrome (example, Laugel_2010, Figueras-Roca_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence reporting a defective transcription of ATF3 responsive genes (CDK5RAP2, NIPBL and NRG1) in patient derived cell lines harboring this variant, as a potential biomarker for Cockayne Syndrome (Epanchintsev_2020). The following publications have been ascertained in the context of this evaluation (PMID: 29572252, 31980658, 30820731, 19894250, 30871974). ClinVar contains an entry for this variant (Variation ID: 68753). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Cockayne syndrome type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Dec 23, 2016

- -

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.045	D;.
Polyphen		0.98	D;.
Vest4		0.97
MutPred		0.46		Gain of glycosylation at A160 (P = 0.0462);.;
MVP		0.89
MPC		0.16
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.75
gMVP		0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs281875222; hg19: chr5-60200622;