rs41281674

Variant names:

• chr13-102872396-A-C
• rs41281674
• NM_000123.4:c.2877A>C

Your query was ambiguous. Multiple possible variants found:

• chr13-102872396-A-C
• chr13-102872396-A-G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001204425.2(BIVM-ERCC5):​c.4239A>C​(p.Arg1413Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000627 in 1,614,174 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: BIVM-ERCC5 NM_001204425.2 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:2 O:1
• Conservation: PhyloP100: 3.91
• Publications: 3 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010380447).
• BP6: Variant 13-102872396-A-C is Benign according to our data. Variant chr13-102872396-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204425.2. 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.2877A>C	p.Arg959Ser	missense splice_region	Exon 13 of 15	NP_000114.3
	BIVM-ERCC5	NM_001204425.2		c.4239A>C	p.Arg1413Ser	missense splice_region	Exon 21 of 23	NP_001191354.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC5	ENST00000652225.2	MANE Select	c.2877A>C	p.Arg959Ser	missense splice_region	Exon 13 of 15	ENSP00000498881.2
	BIVM-ERCC5	ENST00000639435.1	TSL:5	c.4239A>C	p.Arg1413Ser	missense splice_region	Exon 23 of 25	ENSP00000491742.1
	BIVM-ERCC5	ENST00000639132.1	TSL:5	c.3552A>C	p.Arg1184Ser	missense splice_region	Exon 22 of 24	ENSP00000492684.1

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 521 AN: 152190 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00103 AC: 258 AN: 251364 AF XY: 0.000846

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000337 AC: 493 AN: 1461866 Hom.: 1 Cov.: 31 AF XY: 0.000305 AC XY: 222 AN XY: 727230

African (AFR) AF: 0.0108 AC: 361 AN: 33480

American (AMR) AF: 0.000894 AC: 40 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1112002

Other (OTH) AF: 0.000894 AC: 54 AN: 60396

GnomAD4 genome AF: 0.00341 AC: 519 AN: 152308 Hom.: 3 Cov.: 32 AF XY: 0.00318 AC XY: 237 AN XY: 74474

African (AFR) AF: 0.0118 AC: 492 AN: 41578

American (AMR) AF: 0.00118 AC: 18 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00134 Hom.: 5

Bravo AF: 0.00414

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00123 AC: 150

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	0.012
Eigen_PC	Benign	0.081
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.9
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.26	B
Vest4		0.76
MutPred		0.59		Gain of catalytic residue at R964 (P = 0.001)
MVP		0.90
MPC		0.15
ClinPred		0.087	T
GERP RS		3.1
Varity_R		0.77
gMVP		0.68
Mutation Taster		=83/17	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: rs41281674; hg19: chr13-103524746; COSMIC: COSV63245437;