rs4150342

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000123.4(ERCC5):ā€‹c.2636A>Gā€‹(p.Asn879Ser) 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 (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0093 ( 13 hom., cov: 32)
Exomes š‘“: 0.012 ( 121 hom. )

Consequence

ERCC5
NM_000123.4 missense

Scores

1
3
13

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 9.21
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 134162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-102868215-A-G is described in Lovd as [Benign].
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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ERCC5NM_000123.4 linkuse as main transcriptc.2636A>G p.Asn879Ser missense_variant 12/15 ENST00000652225.2 NP_000114.3 P28715-1
BIVM-ERCC5NM_001204425.2 linkuse as main transcriptc.3998A>G p.Asn1333Ser missense_variant 20/23 NP_001191354.2 R4GMW8Q59FZ7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ERCC5ENST00000652225.2 linkuse as main transcriptc.2636A>G p.Asn879Ser missense_variant 12/15 NM_000123.4 ENSP00000498881.2 P28715-1
BIVM-ERCC5ENST00000639435.1 linkuse as main transcriptc.3998A>G p.Asn1333Ser missense_variant 22/255 ENSP00000491742.1 R4GMW8
BIVM-ERCC5ENST00000639132.1 linkuse as main transcriptc.3311A>G p.Asn1104Ser missense_variant 21/245 ENSP00000492684.1 A0A1W2PS85

Frequencies

GnomAD3 genomes
AF:
0.00933
AC:
1421
AN:
152240
Hom.:
13
Cov.:
32
show subpopulations
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
GnomAD3 exomes
AF:
0.00987
AC:
2482
AN:
251464
Hom.:
13
AF XY:
0.00991
AC XY:
1347
AN XY:
135914
show subpopulations
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 SAS exome
AF:
0.00467
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
show subpopulations
Gnomad4 AFR exome
AF:
0.00221
Gnomad4 AMR exome
AF:
0.0115
Gnomad4 ASJ exome
AF:
0.00980
Gnomad4 EAS exome
AF:
0.000151
Gnomad4 SAS exome
AF:
0.00460
Gnomad4 FIN exome
AF:
0.00760
Gnomad4 NFE exome
AF:
0.0134
Gnomad4 OTH exome
AF:
0.0112
GnomAD4 genome
AF:
0.00933
AC:
1422
AN:
152358
Hom.:
13
Cov.:
32
AF XY:
0.00973
AC XY:
725
AN XY:
74512
show subpopulations
Gnomad4 AFR
AF:
0.00236
Gnomad4 AMR
AF:
0.0180
Gnomad4 ASJ
AF:
0.00865
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00496
Gnomad4 FIN
AF:
0.00828
Gnomad4 NFE
AF:
0.0129
Gnomad4 OTH
AF:
0.0109
Alfa
AF:
0.0124
Hom.:
30
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

Significance: Benign
Submissions summary: Benign:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:5
Likely benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The ERCC5 p.Asn879Ser variant was identified in dbSNP (ID: rs4150342) and ClinVar (submitted by ITMI with no classification) but was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 2751 of 282866 chromosomes (15 homozygous) at a frequency of 0.009725 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 1776 of 129182 chromosomes (freq: 0.01375), Latino in 384 of 35438 chromosomes (freq: 0.01084), Other in 77 of 7224 chromosomes (freq: 0.01066), Ashkenazi Jewish in 95 of 10370 chromosomes (freq: 0.009161), European (Finnish) in 218 of 25122 chromosomes (freq: 0.008678), South Asian in 143 of 30616 chromosomes (freq: 0.004671), African in 56 of 24964 chromosomes (freq: 0.002243), and East Asian in 2 of 19950 chromosomes (freq: 0.0001). The variant was identified in a patient with Xeroderma Pigmentosum who also carried multiple other ERCC5 variants, therefore the N879S variant was not expected to have functional significance (Lalle_2002_PMID:11841555). The p.Asn879 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 24, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxMay 29, 2019This variant is associated with the following publications: (PMID: 11841555, 24728327) -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2024BIVM-ERCC5: BP4, BS1, BS2; ERCC5: BP4, BS1, BS2 -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Xeroderma pigmentosum, group G Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
not specified Other:1
not provided, no classification providedreference populationITMISep 19, 2013- -

Computational scores

Source: dbNSFP v4.3

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;D;.;D;D
MetaRNN
Benign
0.0091
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.4
.;.;.;L;.
PROVEAN
Uncertain
-2.6
.;.;.;D;N
REVEL
Benign
0.23
Sift
Benign
0.32
.;.;.;T;T
Sift4G
Benign
0.28
.;.;.;T;T
Polyphen
0.52
.;.;.;P;.
Vest4
0.59, 0.67
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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs4150342; hg19: chr13-103520565; COSMIC: COSV100863589; API