rs254942

chr16-13932150-G-Achr16-13932150-G-Cchr16-13932150-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005236.3(ERCC4):c.974-7G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.976 in 1,612,468 control chromosomes in the GnomAD database, including 769,252 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (72873 hom., cov: 32)
  • Exomes 𝑓: 0.98 (696379 hom.)
• Consequence: ERCC4 NM_005236.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001776
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.96

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 16-13932150-G-A is Benign according to our data. Variant chr16-13932150-G-A is described in ClinVar as [Benign]. Clinvar id is 259686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-13932150-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.987 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC4	NM_005236.3	c.974-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000311895.8
ERCC4	XM_011522424.4	c.1112-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ERCC4	XM_047433774.1	c.185-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC4	ENST00000311895.8	c.974-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005236.3	P1
	ENST00000570663.1	n.220-1297C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.977 AC: 148762 AN: 152224 Hom.: 72814 Cov.: 32

Gnomad AFR AF: 0.995

Gnomad AMI AF: 0.962

Gnomad AMR AF: 0.985

Gnomad ASJ AF: 0.971

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.977

Gnomad FIN AF: 0.977

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.980

Gnomad OTH AF: 0.979

GnomAD3 exomes AF: 0.966 AC: 242632 AN: 251260 Hom.: 117506 AF XY: 0.967 AC XY: 131308 AN XY: 135838

Gnomad AFR exome AF: 0.996

Gnomad AMR exome AF: 0.976

Gnomad ASJ exome AF: 0.967

Gnomad EAS exome AF: 0.787

Gnomad SAS exome AF: 0.978

Gnomad FIN exome AF: 0.979

Gnomad NFE exome AF: 0.981

Gnomad OTH exome AF: 0.976

GnomAD4 exome AF: 0.976 AC: 1425233 AN: 1460126 Hom.: 696379 Cov.: 38 AF XY: 0.976 AC XY: 709305 AN XY: 726558

Gnomad4 AFR exome AF: 0.997

Gnomad4 AMR exome AF: 0.977

Gnomad4 ASJ exome AF: 0.968

Gnomad4 EAS exome AF: 0.793

Gnomad4 SAS exome AF: 0.978

Gnomad4 FIN exome AF: 0.979

Gnomad4 NFE exome AF: 0.982

Gnomad4 OTH exome AF: 0.970

GnomAD4 genome AF: 0.977 AC: 148879 AN: 152342 Hom.: 72873 Cov.: 32 AF XY: 0.976 AC XY: 72729 AN XY: 74498

Gnomad4 AFR AF: 0.995

Gnomad4 AMR AF: 0.985

Gnomad4 ASJ AF: 0.971

Gnomad4 EAS AF: 0.777

Gnomad4 SAS AF: 0.977

Gnomad4 FIN AF: 0.977

Gnomad4 NFE AF: 0.980

Gnomad4 OTH AF: 0.979

Alfa AF: 0.980 Hom.: 92636

Bravo AF: 0.976

Asia WGS AF: 0.910 AC: 3165 AN: 3478

EpiCase AF: 0.980

EpiControl AF: 0.981

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum, group F Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

XFE progeroid syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Fanconi anemia complementation group Q Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 14, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	0.010
Dann	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.0020
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: rs254942; hg19: chr16-14026007;