NM_000082.4:c.478G>A

Variant names:

• chr5-60904795-C-T
• rs281875222
• NM_000082.4:c.478G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM2 PM5 PP3 PP5_Very_Strong

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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005039920: "At least one publication reports experimental evidence reporting a defective transcription of ATF3 responsive genes (CDK5RAP2, NIPBL and NRG1) in patient derived cell lines harboring this variant, as a potential biomarker for Cockayne Syndrome (Epanchintsev_2020)." PMID:29572252, 31980658, 30820731, 19894250, 30871974". 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: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1 O:1
• Conservation: PhyloP100: 6.57
• Publications: 3 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: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005039920: "At least one publication reports experimental evidence reporting a defective transcription of ATF3 responsive genes (CDK5RAP2, NIPBL and NRG1) in patient derived cell lines harboring this variant, as a potential biomarker for Cockayne Syndrome (Epanchintsev_2020)." PMID: 29572252, 31980658, 30820731, 19894250, 30871974
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 1717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 Likely_pathogenic. ClinVar VariationId is 68753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.478G>A	p.Ala160Thr	missense	Exon 5 of 12	NP_000073.1	Q13216-1
	ERCC8	NM_001007233.3		c.304G>A	p.Ala102Thr	missense	Exon 6 of 13	NP_001007234.1	B3KPW7
	ERCC8	NM_001007234.3		c.478G>A	p.Ala160Thr	missense	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.478G>A	p.Ala160Thr	missense	Exon 5 of 12	ENSP00000501614.1	Q13216-1
	ERCC8	ENST00000265038.10	TSL:1	c.478G>A	p.Ala160Thr	missense	Exon 5 of 13	ENSP00000265038.6	A0A7I2PE23
	ERCC8	ENST00000497892.6	TSL:1	n.*276G>A		non_coding_transcript_exon	Exon 6 of 7	ENSP00000501805.1	A0A6Q8PFI5

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 250786 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000348 AC: 5 AN: 1437276 Hom.: 0 Cov.: 25 AF XY: 0.00000558 AC XY: 4 AN XY: 716542

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33086

American (AMR) AF: 0.0000673 AC: 3 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25902

East Asian (EAS) AF: 0.00 AC: 0 AN: 39408

South Asian (SAS) AF: 0.00 AC: 0 AN: 85488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1090358

Other (OTH) AF: 0.00 AC: 0 AN: 59502

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000707758), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150594 Hom.: 0 Cov.: 26 AF XY: 0.0000136 AC XY: 1 AN XY: 73426

African (AFR) AF: 0.00 AC: 0 AN: 41102

American (AMR) AF: 0.0000663 AC: 1 AN: 15090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67646

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Cockayne syndrome (1)
-	1	-	Cockayne syndrome type 1 (1)
1	-	-	Cockayne syndrome type 1;C3553298:UV-sensitive syndrome 2 (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0080	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
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs281875222; hg19: chr5-60200622;