13-102875178-A-T

Variant names:

• chr13-102875178-A-T
• rs4150386
• NM_000123.4:c.2965-129A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000123.4(ERCC5):​c.2965-129A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000108 in 925,598 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: ERCC5 NM_000123.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.180
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000123.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC5	NM_000123.4	MANE Select	c.2965-129A>T		intron	N/A	NP_000114.3
	BIVM-ERCC5	NM_001204425.2		c.4327-129A>T		intron	N/A	NP_001191354.2	R4GMW8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC5	ENST00000652225.2	MANE Select	c.2965-129A>T		intron	N/A	ENSP00000498881.2	P28715-1
	BIVM-ERCC5	ENST00000639435.1	TSL:5	c.4327-129A>T		intron	N/A	ENSP00000491742.1	R4GMW8
	BIVM-ERCC5	ENST00000639132.1	TSL:5	c.3640-129A>T		intron	N/A	ENSP00000492684.1	A0A1W2PS85

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000108 AC: 1 AN: 925598 Hom.: 0 AF XY: 0.00000213 AC XY: 1 AN XY: 468996

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21194

American (AMR) AF: 0.00 AC: 0 AN: 24622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18432

East Asian (EAS) AF: 0.00 AC: 0 AN: 33230

South Asian (SAS) AF: 0.00 AC: 0 AN: 58368

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2978

European-Non Finnish (NFE) AF: 0.00000146 AC: 1 AN: 685872

Other (OTH) AF: 0.00 AC: 0 AN: 41530

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.8
DANN	Benign	0.72
PhyloP100		0.18

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: rs4150386; hg19: chr13-103527528;