rs878854403

Variant names:

• chr10-49516282-C-T
• rs878854403
• NM_001277058.2:c.2237G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 3 publications found

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:19400): (piggyBac transposable element derived 3) This gene is a member of a small family of genes derived from piggyBac transposable elements. The encoded protein contains a zinc-ribbon domain characteristic of transposon-derived proteins and may function as a regulator of transcription. Alternative splicing occurs between a splice site from exon 5 of the adjacent upstream gene 'excision repair cross-complementation group 6' (ERCC6, GeneID: 2074) and the 3' splice site upstream of the open reading frame (ORF) of this gene, 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. Pseudogenes for this gene are defined on chromosomes 4, 5 and 12. [provided by RefSeq, Mar 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId is 225904.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277058.2. 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
	ERCC6	NM_001277058.2	MANE Plus Clinical	c.2237G>A	p.Gly746Asp	missense	Exon 6 of 6	NP_001263987.1	P0DP91-1
	ERCC6	NM_000124.4	MANE Select	c.1397+7751G>A		intron	N/A	NP_000115.1	Q03468-1
	ERCC6	NM_001277059.2		c.2237G>A	p.Gly746Asp	missense	Exon 6 of 6	NP_001263988.1	P0DP91-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	ENST00000447839.7	TSL:2 MANE Plus Clinical	c.2237G>A	p.Gly746Asp	missense	Exon 6 of 6	ENSP00000387966.2	P0DP91-1
	ERCC6	ENST00000355832.10	TSL:1 MANE Select	c.1397+7751G>A		intron	N/A	ENSP00000348089.5	Q03468-1
	ERCC6	ENST00000515869.1	TSL:2	c.2237G>A	p.Gly746Asp	missense	Exon 6 of 6	ENSP00000423550.1	P0DP91-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Premature ovarian failure 11 (1)

Computational scores

Source: dbNSFP v4.9

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
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0055	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-1.0	T
PhyloP100		1.6
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.19
Sift	Benign	0.14	T
Sift4G	Uncertain	0.031	D
Vest4		0.34
MutPred		0.82		Gain of relative solvent accessibility (P = 0.0215)
MVP		0.040
MPC		0.27
ClinPred		0.89	D
GERP RS		0.47
Mutation Taster		=17/83	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: rs878854403; hg19: chr10-50724328;