rs786205573

Variant names:

• chr5-60890914-C-T
• rs786205573
• NM_000082.4:c.1016G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_000082.4(ERCC8):​c.1016G>A​(p.Cys339Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. C339G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ERCC8 NM_000082.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.32
• Publications: 1 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: Laboratory for Molecular Medicine, Genomics England PanelApp, PanelApp Australia, ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903
• PP5: Variant 5-60890914-C-T is Pathogenic according to our data. Variant chr5-60890914-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191197.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC8	NM_000082.4	c.1016G>A	p.Cys339Tyr	missense_variant	Exon 10 of 12	ENST00000676185.1	NP_000073.1
ERCC8	NM_001007233.3	c.842G>A	p.Cys281Tyr	missense_variant	Exon 11 of 13		NP_001007234.1
ERCC8	NM_001290285.2	c.557G>A	p.Cys186Tyr	missense_variant	Exon 9 of 11		NP_001277214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC8	ENST00000676185.1	c.1016G>A	p.Cys339Tyr	missense_variant	Exon 10 of 12		NM_000082.4	ENSP00000501614.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

-

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.73		Loss of catalytic residue at V341 (P = 0.1213);
MVP		0.95
MPC		0.44
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.98
gMVP		0.70
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs786205573; hg19: chr5-60186741;