rs4150342

Variant names:

• chr13-102868215-A-G
• rs4150342
• NM_000123.4:c.2636A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001204425.2(BIVM-ERCC5):​c.3998A>G​(p.Asn1333Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,614,222 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (13 hom., cov: 32)
  • Exomes 𝑓: 0.012 (121 hom.)
• Consequence: BIVM-ERCC5 NM_001204425.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 9.21
• Publications: 23 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009051204).
• BP6: Variant 13-102868215-A-G is Benign according to our data. Variant chr13-102868215-A-G is described in ClinVar as Benign. ClinVar VariationId is 134162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00933 (1422/152358) while in subpopulation AMR AF = 0.018 (276/15302). AF 95% confidence interval is 0.0163. There are 13 homozygotes in GnomAd4. There are 725 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.2636A>G	p.Asn879Ser	missense	Exon 12 of 15	NP_000114.3
	BIVM-ERCC5	NM_001204425.2		c.3998A>G	p.Asn1333Ser	missense	Exon 20 of 23	NP_001191354.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC5	ENST00000652225.2	MANE Select	c.2636A>G	p.Asn879Ser	missense	Exon 12 of 15	ENSP00000498881.2
	BIVM-ERCC5	ENST00000639435.1	TSL:5	c.3998A>G	p.Asn1333Ser	missense	Exon 22 of 25	ENSP00000491742.1
	BIVM-ERCC5	ENST00000639132.1	TSL:5	c.3311A>G	p.Asn1104Ser	missense	Exon 21 of 24	ENSP00000492684.1

Frequencies

GnomAD3 genomes AF: 0.00933 AC: 1421 AN: 152240 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00236

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00475

Gnomad FIN AF: 0.00828

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00987 AC: 2482 AN: 251464 AF XY: 0.00991

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.00933

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00859

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0118 AC: 17314 AN: 1461864 Hom.: 121 Cov.: 31 AF XY: 0.0117 AC XY: 8479 AN XY: 727230

African (AFR) AF: 0.00221 AC: 74 AN: 33480

American (AMR) AF: 0.0115 AC: 515 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 256 AN: 26132

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39690

South Asian (SAS) AF: 0.00460 AC: 397 AN: 86258

European-Finnish (FIN) AF: 0.00760 AC: 406 AN: 53418

Middle Eastern (MID) AF: 0.0191 AC: 110 AN: 5768

European-Non Finnish (NFE) AF: 0.0134 AC: 14874 AN: 1112000

Other (OTH) AF: 0.0112 AC: 676 AN: 60394

GnomAD4 genome AF: 0.00933 AC: 1422 AN: 152358 Hom.: 13 Cov.: 32 AF XY: 0.00973 AC XY: 725 AN XY: 74512

African (AFR) AF: 0.00236 AC: 98 AN: 41590

American (AMR) AF: 0.0180 AC: 276 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00496 AC: 24 AN: 4834

European-Finnish (FIN) AF: 0.00828 AC: 88 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0129 AC: 879 AN: 68036

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.0120 Hom.: 60

Bravo AF: 0.00966

TwinsUK AF: 0.0156 AC: 58

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.0140 AC: 120

ExAC AF: 0.00951 AC: 1155

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0133

EpiControl AF: 0.0151

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Xeroderma pigmentosum, group G (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.013
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		9.2
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.23
Sift	Benign	0.32	T
Sift4G	Benign	0.28	T
Polyphen		0.52	P
Vest4		0.59
MVP		0.66
MPC		0.50
ClinPred		0.021	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.40
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4150342; hg19: chr13-103520565;