NM_000082.4:c.435T>C

Variant names:

• chr5-60904838-A-G
• rs4647100
• NM_000082.4:c.435T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000082.4(ERCC8):​c.435T>C​(p.Tyr145Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 1,587,156 control chromosomes in the GnomAD database, including 50,035 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3499 hom., cov: 27)
  • Exomes 𝑓: 0.25 (46536 hom.)
• Consequence: ERCC8 NM_000082.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.62
• Publications: 17 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 Gene-Disease associations (from GenCC):

• Cockayne syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, Myriad Women’s Health, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• UV-sensitive syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• Cockayne syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• UV-sensitive syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 5-60904838-A-G is Benign according to our data. Variant chr5-60904838-A-G is described in ClinVar as Benign. ClinVar VariationId is 190177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

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.435T>C	p.Tyr145Tyr	synonymous	Exon 5 of 12	NP_000073.1	Q13216-1
	ERCC8	NM_001007233.3		c.261T>C	p.Tyr87Tyr	synonymous	Exon 6 of 13	NP_001007234.1	B3KPW7
	ERCC8	NM_001007234.3		c.435T>C	p.Tyr145Tyr	synonymous	Exon 5 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.435T>C	p.Tyr145Tyr	synonymous	Exon 5 of 12	ENSP00000501614.1	Q13216-1
	ERCC8	ENST00000265038.10	TSL:1	c.435T>C	p.Tyr145Tyr	synonymous	Exon 5 of 13	ENSP00000265038.6	A0A7I2PE23
	ERCC8	ENST00000497892.6	TSL:1	n.*233T>C		non_coding_transcript_exon	Exon 6 of 7	ENSP00000501805.1	A0A6Q8PFI5

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29414 AN: 150696 Hom.: 3498 Cov.: 27

Gnomad AFR AF: 0.0909

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.00330

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.267

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.206

GnomAD2 exomes AF: 0.205 AC: 51442 AN: 251058 AF XY: 0.211

Gnomad AFR exome AF: 0.0854

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.230

Gnomad EAS exome AF: 0.00109

Gnomad FIN exome AF: 0.285

Gnomad NFE exome AF: 0.262

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.246 AC: 352696 AN: 1436350 Hom.: 46536 Cov.: 25 AF XY: 0.246 AC XY: 175846 AN XY: 715992

African (AFR) AF: 0.0806 AC: 2676 AN: 33186

American (AMR) AF: 0.137 AC: 6103 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 6230 AN: 25946

East Asian (EAS) AF: 0.000557 AC: 22 AN: 39466

South Asian (SAS) AF: 0.195 AC: 16743 AN: 85650

European-Finnish (FIN) AF: 0.280 AC: 14929 AN: 53276

Middle Eastern (MID) AF: 0.222 AC: 1269 AN: 5712

European-Non Finnish (NFE) AF: 0.267 AC: 291061 AN: 1088946

Other (OTH) AF: 0.229 AC: 13663 AN: 59548

GnomAD4 genome AF: 0.195 AC: 29417 AN: 150806 Hom.: 3499 Cov.: 27 AF XY: 0.194 AC XY: 14308 AN XY: 73676

African (AFR) AF: 0.0908 AC: 3747 AN: 41282

American (AMR) AF: 0.180 AC: 2721 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 818 AN: 3456

East Asian (EAS) AF: 0.00331 AC: 17 AN: 5140

South Asian (SAS) AF: 0.193 AC: 922 AN: 4772

European-Finnish (FIN) AF: 0.267 AC: 2715 AN: 10166

Middle Eastern (MID) AF: 0.202 AC: 59 AN: 292

European-Non Finnish (NFE) AF: 0.265 AC: 17890 AN: 67552

Other (OTH) AF: 0.203 AC: 425 AN: 2092

Alfa AF: 0.234 Hom.: 2233

Bravo AF: 0.184

Asia WGS AF: 0.0790 AC: 276 AN: 3454

EpiCase AF: 0.267

EpiControl AF: 0.257

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.46
PhyloP100		1.6
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: -46

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4647100; hg19: chr5-60200665; COSMIC: COSV54015563;