rs3136202

Variant names:

• chr16-13944317-G-A
• rs3136202
• NM_005236.3:c.1905-406G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005236.3(ERCC4):​c.1905-406G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 151,760 control chromosomes in the GnomAD database, including 14,525 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.41 (14525 hom., cov: 32)
• Consequence: ERCC4 NM_005236.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.95
• Publications: 23 publications found

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 Gene-Disease associations (from GenCC):

• xeroderma pigmentosum group F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, ClinGen
• Fanconi anemia complementation group Q

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• XFE progeroid syndrome

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum-Cockayne syndrome complex

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC4	NM_005236.3	c.1905-406G>A		intron_variant	Intron 9 of 10	ENST00000311895.8	NP_005227.1
ERCC4	XM_011522424.4	c.2043-406G>A		intron_variant	Intron 10 of 11		XP_011520726.1
ERCC4	XM_047433774.1	c.1116-406G>A		intron_variant	Intron 6 of 7		XP_047289730.1
ERCC4	XM_011522427.2	c.555-406G>A		intron_variant	Intron 4 of 5		XP_011520729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8	c.1905-406G>A		intron_variant	Intron 9 of 10	1	NM_005236.3	ENSP00000310520.7

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62493 AN: 151642 Hom.: 14483 Cov.: 32

Gnomad AFR AF: 0.630

Gnomad AMI AF: 0.429

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.411

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.412 AC: 62588 AN: 151760 Hom.: 14525 Cov.: 32 AF XY: 0.406 AC XY: 30078 AN XY: 74148

African (AFR) AF: 0.631 AC: 26119 AN: 41402

American (AMR) AF: 0.302 AC: 4612 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1353 AN: 3468

East Asian (EAS) AF: 0.248 AC: 1278 AN: 5158

South Asian (SAS) AF: 0.273 AC: 1309 AN: 4794

European-Finnish (FIN) AF: 0.311 AC: 3247 AN: 10452

Middle Eastern (MID) AF: 0.428 AC: 125 AN: 292

European-Non Finnish (NFE) AF: 0.343 AC: 23287 AN: 67912

Other (OTH) AF: 0.412 AC: 867 AN: 2106

Alfa AF: 0.362 Hom.: 36680

Bravo AF: 0.423

Asia WGS AF: 0.320 AC: 1114 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.17
DANN	Benign	0.45
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3136202; hg19: chr16-14038174;