rs4647088

chr5-60918301-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000082.4(ERCC8):c.363T>C(p.Asp121=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,598,376 control chromosomes in the GnomAD database, including 324 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (19 hom., cov: 32)
  • Exomes 𝑓: 0.019 (305 hom.)
• Consequence: ERCC8 NM_000082.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.38

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-AS1 (HGNC:40220): (ERCC8 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 5-60918301-A-G is Benign according to our data. Variant chr5-60918301-A-G is described in ClinVar as [Benign]. Clinvar id is 190176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-60918301-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=3.38 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0131 (1998/152216) while in subpopulation NFE AF= 0.0215 (1460/67970). AF 95% confidence interval is 0.0206. There are 19 homozygotes in gnomad4. There are 912 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC8	NM_000082.4	c.363T>C	p.Asp121=	synonymous_variant	4/12	ENST00000676185.1
ERCC8-AS1	NR_183288.1	n.386A>G		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC8	ENST00000676185.1	c.363T>C	p.Asp121=	synonymous_variant	4/12		NM_000082.4	P1
ERCC8-AS1	ENST00000457499.1	n.85A>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1999 AN: 152098 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00350

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.0150 AC: 3751 AN: 250230 Hom.: 48 AF XY: 0.0159 AC XY: 2150 AN XY: 135252

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0220

Gnomad FIN exome AF: 0.00372

Gnomad NFE exome AF: 0.0208

Gnomad OTH exome AF: 0.0212

GnomAD4 exome AF: 0.0191 AC: 27650 AN: 1446160 Hom.: 305 Cov.: 27 AF XY: 0.0194 AC XY: 13963 AN XY: 720530

Gnomad4 AFR exome AF: 0.00365

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0193

Gnomad4 FIN exome AF: 0.00439

Gnomad4 NFE exome AF: 0.0215

Gnomad4 OTH exome AF: 0.0187

GnomAD4 genome AF: 0.0131 AC: 1998 AN: 152216 Hom.: 19 Cov.: 32 AF XY: 0.0123 AC XY: 912 AN XY: 74440

Gnomad4 AFR AF: 0.00349

Gnomad4 AMR AF: 0.0135

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0178

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.0215

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0180 Hom.: 30

Bravo AF: 0.0136

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0224

EpiControl AF: 0.0226

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Claritas Genomics	Nov 16, 2012	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2019	- -

Cockayne syndrome type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
Cadd	Benign	16
Dann	Benign	0.85

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: rs4647088; hg19: chr5-60214128;