16-13920198-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005236.3(ERCC4):c.33C>T(p.Ala11=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,607,076 control chromosomes in the GnomAD database, including 398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (19 hom., cov: 33)
  • Exomes 𝑓: 0.021 (379 hom.)
• Consequence: ERCC4 NM_005236.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.10

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 16-13920198-C-T is Benign according to our data. Variant chr16-13920198-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 240125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-13920198-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.11 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0136 (2074/152360) while in subpopulation NFE AF= 0.0229 (1557/68036). AF 95% confidence interval is 0.0219. There are 19 homozygotes in gnomad4. There are 913 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC4	NM_005236.3	c.33C>T	p.Ala11=	synonymous_variant	1/11	ENST00000311895.8
LOC105371093	XR_007065000.1	n.82+6327G>A		intron_variant, non_coding_transcript_variant
ERCC4	XM_011522424.4	c.33C>T	p.Ala11=	synonymous_variant	1/12
LOC105371093	XR_007064999.1	n.82+6327G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC4	ENST00000311895.8	c.33C>T	p.Ala11=	synonymous_variant	1/11	1	NM_005236.3	P1

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2068 AN: 152242 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.00562

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00824

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00856

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.0128 AC: 3131 AN: 243880 Hom.: 42 AF XY: 0.0125 AC XY: 1668 AN XY: 132934

Gnomad AFR exome AF: 0.00470

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.00758

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00222

Gnomad FIN exome AF: 0.00913

Gnomad NFE exome AF: 0.0228

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.0206 AC: 29950 AN: 1454716 Hom.: 379 Cov.: 35 AF XY: 0.0197 AC XY: 14266 AN XY: 724034

Gnomad4 AFR exome AF: 0.00436

Gnomad4 AMR exome AF: 0.00445

Gnomad4 ASJ exome AF: 0.00853

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00186

Gnomad4 FIN exome AF: 0.0105

Gnomad4 NFE exome AF: 0.0250

Gnomad4 OTH exome AF: 0.0155

GnomAD4 genome AF: 0.0136 AC: 2074 AN: 152360 Hom.: 19 Cov.: 33 AF XY: 0.0123 AC XY: 913 AN XY: 74508

Gnomad4 AFR AF: 0.00575

Gnomad4 AMR AF: 0.00823

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00856

Gnomad4 NFE AF: 0.0229

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.0199 Hom.: 28

Bravo AF: 0.0134

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0218

EpiControl AF: 0.0179

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum, group F Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 12, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	4.0
Dann	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs3136042; hg19: chr16-14014055; COSMIC: COSV61313691; COSMIC: COSV61313691;