NM_000082.4:c.479C>G

Variant names:

• chr5-60904794-G-C
• rs121434325
• NM_000082.4:c.479C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_000082.4(ERCC8):​c.479C>G​(p.Ala160Gly) variant causes a missense, splice region 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 26)
• Consequence: ERCC8 NM_000082.4 missense, splice_region
• Scores: Splicing: ADA: 0.9933
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.33
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• 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 [Likely_pathogenic]. Clinvar id is 1717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC8	NM_000082.4	c.479C>G	p.Ala160Gly	missense_variant, splice_region_variant	Exon 5 of 12	ENST00000676185.1	NP_000073.1
ERCC8	NM_001007233.3	c.305C>G	p.Ala102Gly	missense_variant, splice_region_variant	Exon 6 of 13		NP_001007234.1
ERCC8	NM_001007234.3	c.479C>G	p.Ala160Gly	missense_variant, splice_region_variant	Exon 5 of 6		NP_001007235.1
ERCC8	NM_001290285.2	c.23-1078C>G		intron_variant	Intron 4 of 10		NP_001277214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC8	ENST00000676185.1	c.479C>G	p.Ala160Gly	missense_variant, splice_region_variant	Exon 5 of 12		NM_000082.4	ENSP00000501614.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.8	M;.
PhyloP100		8.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0020	D;.
Polyphen		0.98	D;.
Vest4		0.82
MutPred		0.41		Gain of loop (P = 0.1069);.;
MVP		0.88
MPC		0.27
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.78
gMVP		0.47
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.25		Position offset: -2

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

Other links and lift over

dbSNP: rs121434325; hg19: chr5-60200621;