rs4771436

Variant names:

• chr13-102849670-T-G
• rs4771436
• NM_000123.4:c.89-2448T>G

Variant summary

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

The NM_000123.4(ERCC5):​c.89-2448T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 152,118 control chromosomes in the GnomAD database, including 4,102 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 0.22 (4102 hom., cov: 32)
• Consequence: ERCC5 NM_000123.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.601
• Publications: 21 publications found

Genes affected

ERCC5 (HGNC:3437): (ERCC excision repair 5, endonuclease) This gene encodes a single-strand specific DNA endonuclease that makes the 3' incision in DNA excision repair following UV-induced damage. The protein may also function in other cellular processes, including RNA polymerase II transcription, and transcription-coupled DNA repair. Mutations in this gene cause xeroderma pigmentosum complementation group G (XP-G), which is also referred to as xeroderma pigmentosum VII (XP7), a skin disorder characterized by hypersensitivity to UV light and increased susceptibility for skin cancer development following UV exposure. Some patients also develop Cockayne syndrome, which is characterized by severe growth defects, cognitive disability, and cachexia. Read-through transcription exists between this gene and the neighboring upstream BIVM (basic, immunoglobulin-like variable motif containing) gene. [provided by RefSeq, Feb 2011]

BIVM-ERCC5 (HGNC:43690): (BIVM-ERCC5 readthrough) This locus represents naturally occurring read-through transcription between the neighboring BIVM (basic, immunoglobulin-like variable motif containing) and ERCC5 (excision repair cross-complementing rodent repair deficiency, complementation group 5) genes on chromosome 13. The read-through transcript encodes a fusion protein that shares sequence identity with the products of each individual gene. [provided by RefSeq, Feb 2011]

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 (EAS) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC5	NM_000123.4	c.89-2448T>G		intron_variant	Intron 1 of 14	ENST00000652225.2	NP_000114.3
BIVM-ERCC5	NM_001204425.2	c.1451-2448T>G		intron_variant	Intron 9 of 22		NP_001191354.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC5	ENST00000652225.2	c.89-2448T>G		intron_variant	Intron 1 of 14		NM_000123.4	ENSP00000498881.2
BIVM-ERCC5	ENST00000639435.1	c.1451-2448T>G		intron_variant	Intron 11 of 24	5		ENSP00000491742.1
BIVM-ERCC5	ENST00000639132.1	c.764-2448T>G		intron_variant	Intron 10 of 23	5		ENSP00000492684.1

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34166 AN: 152000 Hom.: 4098 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.229

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

GnomAD4 genome AF: 0.225 AC: 34174 AN: 152118 Hom.: 4102 Cov.: 32 AF XY: 0.227 AC XY: 16877 AN XY: 74390

African (AFR) AF: 0.168 AC: 6987 AN: 41514

American (AMR) AF: 0.332 AC: 5072 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 563 AN: 3470

East Asian (EAS) AF: 0.342 AC: 1771 AN: 5176

South Asian (SAS) AF: 0.314 AC: 1512 AN: 4820

European-Finnish (FIN) AF: 0.201 AC: 2129 AN: 10578

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.226 AC: 15363 AN: 67972

Other (OTH) AF: 0.227 AC: 479 AN: 2112

Alfa AF: 0.227 Hom.: 5023

Bravo AF: 0.229

Asia WGS AF: 0.295 AC: 1026 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.9
DANN	Benign	0.46
PhyloP100		-0.60
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: rs4771436; hg19: chr13-103502020;