5-60898322-T-G

Position:

• chr5-60898322-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000082.4(ERCC8):​c.797A>C​(p.Asp266Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,390 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D266G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ERCC8 NM_000082.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.48

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a repeat WD 5 (size 39) 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 chr5-60898322-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 68756.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 5-60898322-T-G is Pathogenic according to our data. Variant chr5-60898322-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 973767.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC8	NM_000082.4	c.797A>C	p.Asp266Ala	missense_variant	9/12	ENST00000676185.1
ERCC8	NM_001007233.3	c.623A>C	p.Asp208Ala	missense_variant	10/13
ERCC8	NM_001290285.2	c.338A>C	p.Asp113Ala	missense_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC8	ENST00000676185.1	c.797A>C	p.Asp266Ala	missense_variant	9/12		NM_000082.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251254 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135820

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461390 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cockayne syndrome type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

-

Using trio-exome sequencing and analysis of the genes with the ten highest PEDIA values (PMID: 31164752), a probably pathogenic homozygous missense variant was detected in exon 9 of the ERCCB gene. The name of the variant is: NM_000082: c.797A>C;p.(Asp266Ala) . Both parents carry the variant in heterozygous form. In the population-based database gnomAD this variant is listed once in heterozygous form {allele frequency 0.00000398), in the population-based databases ExAC, 1000Genomes and the Exome Variant Server it is not listed. In the phenotype-related database HGMD the above variant is once listed as pathogenic (PMID : 30111349); in ClinVar and LOVD the variant is not found. In addition, another exchange of the affected amino acid (p.Asp266Gly) has already been published as pathogenic (PMID: 19894250 , 16865293). The mutation prediction programs MutationTaster, SIFT and PolyPhen-2 classify the variant as pathogenic, the CADD score is 27.3. One of the most highly conserved amino acids of the ERCC8 protein, located in a WD protein domain, is affected. The ACMG classification for this variant is: probably pathogenic (Class 4: PM1, PM2, PMS, PP3) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.91		Gain of MoRF binding (P = 0.1152);
MVP		0.98
MPC		0.38
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.86

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: rs281875225; hg19: chr5-60194149;