rs142438319

Variant names:

• chr13-102866343-G-A
• rs142438319
• NM_000123.4:c.2281G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-102866343-G-A
• chr13-102866343-G-C
• chr13-102866343-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000123.4(ERCC5):​c.2281G>A​(p.Ala761Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000932 in 1,614,044 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A761V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (1 hom.)
• Consequence: ERCC5 NM_000123.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7 O:1
• Conservation: PhyloP100: 7.49
• Publications: 6 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16235289).

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.2281G>A	p.Ala761Thr	missense	Exon 10 of 15	NP_000114.3
	BIVM-ERCC5	NM_001204425.2		c.3643G>A	p.Ala1215Thr	missense	Exon 18 of 23	NP_001191354.2	R4GMW8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC5	ENST00000652225.2	MANE Select	c.2281G>A	p.Ala761Thr	missense	Exon 10 of 15	ENSP00000498881.2	P28715-1
	BIVM-ERCC5	ENST00000639435.1	TSL:5	c.3643G>A	p.Ala1215Thr	missense	Exon 20 of 25	ENSP00000491742.1	R4GMW8
	BIVM-ERCC5	ENST00000639132.1	TSL:5	c.2956G>A	p.Ala986Thr	missense	Exon 19 of 24	ENSP00000492684.1	A0A1W2PS85

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000445 AC: 112 AN: 251422 AF XY: 0.000405

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000818

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000960 AC: 1403 AN: 1461842 Hom.: 1 Cov.: 30 AF XY: 0.000942 AC XY: 685 AN XY: 727226

African (AFR) AF: 0.000209 AC: 7 AN: 33474

American (AMR) AF: 0.000358 AC: 16 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00121 AC: 1343 AN: 1111984

Other (OTH) AF: 0.000563 AC: 34 AN: 60388

GnomAD4 genome AF: 0.000664 AC: 101 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.000592 AC XY: 44 AN XY: 74354

African (AFR) AF: 0.000482 AC: 20 AN: 41454

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 68034

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000869 Hom.: 0

Bravo AF: 0.000593

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000436 AC: 53

EpiCase AF: 0.000763

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Xeroderma pigmentosum, group G (3)
-	2	-	not provided (2)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Xeroderma pigmentosum, group G;C1851443:Cerebrooculofacioskeletal syndrome 3 (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.5
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.77
MVP		0.55
MPC		0.53
ClinPred		0.16	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.28
Mutation Taster		=56/44	polymorphism

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: rs142438319; hg19: chr13-103518693; COSMIC: COSV104673137;