rs281875222

chr5-60904795-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 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 Likely 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 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a strand (size 14) in uniprot entity ERCC8_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000082.4
• 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 ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1717.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, not_provided=1, Uncertain_significance=1, Pathogenic=1}.
• 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: {Likely_pathogenic=2, not_provided=1, Uncertain_significance=1}. Variant chr5-60904795-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC8	ENST00000676185.1	c.478G>A	p.Ala160Thr	missense_variant	5/12		NM_000082.4	P1

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: Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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;.
MutationTaster	Benign	1.0	D;D;D
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;