NM_000082.4:c.363T>C

Variant names:

• chr5-60918301-A-G
• rs4647088
• NM_000082.4:c.363T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000082.4(ERCC8):​c.363T>C​(p.Asp121Asp) 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:6
• Conservation: PhyloP100: 3.38
• Publications: 5 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 190176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000082.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC8	NM_000082.4	MANE Select	c.363T>C	p.Asp121Asp	synonymous	Exon 4 of 12	NP_000073.1	Q13216-1
	ERCC8	NM_001007233.3		c.189T>C	p.Asp63Asp	synonymous	Exon 5 of 13	NP_001007234.1	B3KPW7
	ERCC8	NM_001007234.3		c.363T>C	p.Asp121Asp	synonymous	Exon 4 of 6	NP_001007235.1	Q13216-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC8	ENST00000676185.1	MANE Select	c.363T>C	p.Asp121Asp	synonymous	Exon 4 of 12	ENSP00000501614.1	Q13216-1
	ERCC8	ENST00000265038.10	TSL:1	c.363T>C	p.Asp121Asp	synonymous	Exon 4 of 13	ENSP00000265038.6	A0A7I2PE23
	ERCC8	ENST00000497892.6	TSL:1	n.*161T>C		non_coding_transcript_exon	Exon 5 of 7	ENSP00000501805.1	A0A6Q8PFI5

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

GnomAD2 exomes AF: 0.0150 AC: 3751 AN: 250230 AF XY: 0.0159

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 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

African (AFR) AF: 0.00365 AC: 121 AN: 33114

American (AMR) AF: 0.0104 AC: 465 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 292 AN: 26000

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39586

South Asian (SAS) AF: 0.0193 AC: 1657 AN: 85934

European-Finnish (FIN) AF: 0.00439 AC: 234 AN: 53260

Middle Eastern (MID) AF: 0.0340 AC: 195 AN: 5736

European-Non Finnish (NFE) AF: 0.0215 AC: 23567 AN: 1098090

Other (OTH) AF: 0.0187 AC: 1117 AN: 59858

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

African (AFR) AF: 0.00349 AC: 145 AN: 41562

American (AMR) AF: 0.0135 AC: 206 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4832

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0215 AC: 1460 AN: 67970

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.0174 Hom.: 36

Bravo AF: 0.0136

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0224

EpiControl AF: 0.0226

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Cockayne syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	16
DANN	Benign	0.85
PhyloP100		3.4
Mutation Taster		=88/12	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4647088; hg19: chr5-60214128;