chr16-13922064-G-C

Position:

• chr16-13922064-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005236.3(ERCC4):​c.241G>C​(p.Val81Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ERCC4 NM_005236.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.50

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC4	NM_005236.3	c.241G>C	p.Val81Leu	missense_variant	2/11	ENST00000311895.8	NP_005227.1
ERCC4	XM_011522424.4	c.241G>C	p.Val81Leu	missense_variant	2/12		XP_011520726.1
LOC105371093	XR_007064999.1	n.82+4461C>G		intron_variant
LOC105371093	XR_007065000.1	n.82+4461C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8	c.241G>C	p.Val81Leu	missense_variant	2/11	1	NM_005236.3	ENSP00000310520.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251332 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461622 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	.;T
Eigen	Benign	-0.0066
Eigen_PC	Benign	-0.016
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.2	L;L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.93	.;N
REVEL	Benign	0.26
Sift	Benign	0.11	.;T
Sift4G	Benign	0.064	T;T
Polyphen		0.60	.;P
Vest4		0.58
MutPred		0.35		Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.65
MPC		0.11
ClinPred		0.38	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.74

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: rs55761944; hg19: chr16-14015921;