16-13920166-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_005236.3(ERCC4):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000551 in 1,452,472 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ERCC4 NM_005236.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24

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]

LOC105371093 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC4	NM_005236.3	c.1A>G	p.Met1?	start_lost	1/11	ENST00000311895.8
LOC105371093	XR_007065000.1	n.82+6359T>C		intron_variant, non_coding_transcript_variant
ERCC4	XM_011522424.4	c.1A>G	p.Met1?	start_lost	1/12
LOC105371093	XR_007064999.1	n.82+6359T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC4	ENST00000311895.8	c.1A>G	p.Met1?	start_lost	1/11	1	NM_005236.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000415 AC: 1 AN: 241212 Hom.: 0 AF XY: 0.00000758 AC XY: 1 AN XY: 131940

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: 0.00000551 AC: 8 AN: 1452472 Hom.: 0 Cov.: 34 AF XY: 0.00000830 AC XY: 6 AN XY: 723048

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: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia complementation group Q Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Jan 09, 2023

The ERCC4 c.1A>G (p.Met1?) change results in a A>G substitution at the 1 position of exon 1 of the ERCC4 gene. This results in loss of the initiation codon in a gene for which loss-of-function is a known mechanism of disease, however a downstream methionine exists. This variant has a maximum subpopulation frequency of 0.0033% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) and other start loss variants in ERCC4 are also present in the gnomAD database. To our knowledge, this variant has not been reported in individuals with Fanconi anemia or Xeroderma pigmentosum. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.033
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0010	.;B
Vest4		0.67
MutPred		0.98		Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.89
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.91
gMVP		0.49

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: rs543978998; hg19: chr16-14014023;