rs878853037

Positions:

• chr16-13920254-A-C
• chr16-13920254-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005236.3(ERCC4):​c.89A>C​(p.Asp30Ala) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ERCC4 NM_005236.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.39

Genes affected

ERCC4 (HGNC:3436): (ERCC excision repair 4, endonuclease catalytic subunit) The protein encoded by this gene forms a complex with ERCC1 and is involved in the 5' incision made during nucleotide excision repair. This complex is a structure specific DNA repair endonuclease that interacts with EME1. Defects in this gene are a cause of xeroderma pigmentosum complementation group F (XP-F), or xeroderma pigmentosum VI (XP6).[provided by RefSeq, Mar 2009]

ERCC4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC4	NM_005236.3	c.89A>C	p.Asp30Ala	missense_variant	1/11	ENST00000311895.8	NP_005227.1
ERCC4	XM_011522424.4	c.89A>C	p.Asp30Ala	missense_variant	1/12		XP_011520726.1
LOC105371093	XR_007064999.1	n.82+6271T>G		intron_variant
LOC105371093	XR_007065000.1	n.82+6271T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8	c.89A>C	p.Asp30Ala	missense_variant	1/11	1	NM_005236.3	ENSP00000310520.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Apr 28, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	.;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.74	T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.050	D
MutationAssessor	Pathogenic	3.6	H;H
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.6	.;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.97	.;D
Vest4		0.79
MutPred		0.69		Loss of stability (P = 0.0339);Loss of stability (P = 0.0339);
MVP		0.83
MPC		0.49
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.82
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs878853037; hg19: chr16-14014111;