rs3759500

Variant names:

• chr13-102866494-C-T
• rs3759500
• NM_000123.4:c.2319+113C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000123.4(ERCC5):​c.2319+113C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,606,480 control chromosomes in the GnomAD database, including 45,432 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4077 hom., cov: 33)
  • Exomes 𝑓: 0.23 (41355 hom.)
• Consequence: ERCC5 NM_000123.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.99
• Publications: 5 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 (BayesDel_noAF=-0.92).
• BP6: Variant 13-102866494-C-T is Benign according to our data. Variant chr13-102866494-C-T is described in ClinVar as Benign. ClinVar VariationId is 1245173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC5	NM_000123.4	c.2319+113C>T		intron_variant	Intron 10 of 14	ENST00000652225.2	NP_000114.3
BIVM-ERCC5	NM_001204425.2	c.3681+113C>T		intron_variant	Intron 18 of 22		NP_001191354.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC5	ENST00000652225.2	c.2319+113C>T		intron_variant	Intron 10 of 14		NM_000123.4	ENSP00000498881.2
BIVM-ERCC5	ENST00000639435.1	c.3681+113C>T		intron_variant	Intron 20 of 24	5		ENSP00000491742.1
BIVM-ERCC5	ENST00000639132.1	c.2994+113C>T		intron_variant	Intron 19 of 23	5		ENSP00000492684.1

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34105 AN: 152044 Hom.: 4073 Cov.: 33

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.229

GnomAD4 exome AF: 0.232 AC: 337927 AN: 1454318 Hom.: 41355 Cov.: 32 AF XY: 0.235 AC XY: 169732 AN XY: 723498

African (AFR) AF: 0.171 AC: 5684 AN: 33322

American (AMR) AF: 0.397 AC: 17613 AN: 44360

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 4466 AN: 26066

East Asian (EAS) AF: 0.323 AC: 12798 AN: 39616

South Asian (SAS) AF: 0.313 AC: 26801 AN: 85586

European-Finnish (FIN) AF: 0.207 AC: 10992 AN: 53188

Middle Eastern (MID) AF: 0.252 AC: 1251 AN: 4964

European-Non Finnish (NFE) AF: 0.221 AC: 244425 AN: 1107124

Other (OTH) AF: 0.231 AC: 13897 AN: 60092

GnomAD4 genome AF: 0.224 AC: 34112 AN: 152162 Hom.: 4077 Cov.: 33 AF XY: 0.226 AC XY: 16838 AN XY: 74372

African (AFR) AF: 0.168 AC: 6958 AN: 41524

American (AMR) AF: 0.332 AC: 5080 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 562 AN: 3470

East Asian (EAS) AF: 0.336 AC: 1732 AN: 5152

South Asian (SAS) AF: 0.313 AC: 1512 AN: 4828

European-Finnish (FIN) AF: 0.202 AC: 2137 AN: 10582

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

European-Non Finnish (NFE) AF: 0.226 AC: 15353 AN: 67988

Other (OTH) AF: 0.227 AC: 480 AN: 2116

Alfa AF: 0.225 Hom.: 3998

Bravo AF: 0.229

Asia WGS AF: 0.292 AC: 1015 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.019
DANN	Benign	0.33
PhyloP100		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs3759500; hg19: chr13-103518844;