rs878854403

chr10-49516282-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001277058.2(ERCC6):c.2237G>A(p.Gly746Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERCC6 NM_001277058.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.62

Genes affected

ERCC6 (HGNC:3438): (ERCC excision repair 6, chromatin remodeling factor) This gene encodes a DNA-binding protein that is important in transcription-coupled excision repair. The encoded protein has ATP-stimulated ATPase activity, interacts with several transcription and excision repair proteins, and may promote complex formation at DNA repair sites. Mutations in this gene are associated with Cockayne syndrome type B and cerebrooculofacioskeletal syndrome 1. Alternative splicing occurs between a splice site from exon 5 of this gene to the 3' splice site upstream of the open reading frame (ORF) of the adjacent gene, piggyback-derived-3 (GeneID:267004), which activates the alternative polyadenylation site downstream of the piggyback-derived-3 ORF. The resulting transcripts encode a fusion protein that shares sequence with the product of each individual gene. [provided by RefSeq, Mar 2016]

PGBD3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-49516282-C-T is Pathogenic according to our data. Variant chr10-49516282-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 225904.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC6	NM_001277058.2	c.2237G>A	p.Gly746Asp	missense_variant	6/6	ENST00000447839.7
PGBD3	NM_170753.3	c.833G>A	p.Gly278Asp	missense_variant	2/2
ERCC6	NM_000124.4	c.1397+7751G>A		intron_variant		ENST00000355832.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC6	ENST00000447839.7	c.2237G>A	p.Gly746Asp	missense_variant	6/6	2	NM_001277058.2
ERCC6	ENST00000355832.10	c.1397+7751G>A		intron_variant		1	NM_000124.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Premature ovarian failure 11 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 13, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	12
Dann	Uncertain	0.99
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.16	N
M_CAP	Benign	0.0055	T
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.95	N;N;N
PROVEAN	Benign	-1.4	N;N;D
REVEL	Benign	0.19
Sift	Benign	0.14	T;T;T
Sift4G	Uncertain	0.031	D;D;D
Vest4		0.34
MutPred		0.82		Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);.;
MVP		0.040
MPC		0.27, 0.93
ClinPred		0.89	D
GERP RS		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs878854403; hg19: chr10-50724328;