chr19-45420238-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001983.4(ERCC1):​c.425+86A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 896,490 control chromosomes in the GnomAD database, including 29,466 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 5559 hom., cov: 31)
Exomes 𝑓: 0.25 ( 23907 hom. )

Consequence

ERCC1
NM_001983.4 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.90

Publications

27 publications found
Variant links:
Genes affected
ERCC1 (HGNC:3433): (ERCC excision repair 1, endonuclease non-catalytic subunit) The product of this gene functions in the nucleotide excision repair pathway, and is required for the repair of DNA lesions such as those induced by UV light or formed by electrophilic compounds including cisplatin. The encoded protein forms a heterodimer with the XPF endonuclease (also known as ERCC4), and the heterodimeric endonuclease catalyzes the 5' incision in the process of excising the DNA lesion. The heterodimeric endonuclease is also involved in recombinational DNA repair and in the repair of inter-strand crosslinks. Mutations in this gene result in cerebrooculofacioskeletal syndrome, and polymorphisms that alter expression of this gene may play a role in carcinogenesis. Multiple transcript variants encoding different isoforms have been found for this gene. The last exon of this gene overlaps with the CD3e molecule, epsilon associated protein gene on the opposite strand. [provided by RefSeq, Oct 2009]
ERCC1 Gene-Disease associations (from GenCC):
  • cerebrooculofacioskeletal syndrome 4
    Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
  • Cockayne syndrome type 2
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • COFS syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 19-45420238-T-C is Benign according to our data. Variant chr19-45420238-T-C is described in ClinVar as Benign. ClinVar VariationId is 1286234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ERCC1NM_001983.4 linkc.425+86A>G intron_variant Intron 4 of 9 ENST00000300853.8 NP_001974.1 P07992-1A0A024R0Q6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ERCC1ENST00000300853.8 linkc.425+86A>G intron_variant Intron 4 of 9 1 NM_001983.4 ENSP00000300853.3 P07992-1

Frequencies

GnomAD3 genomes
AF:
0.266
AC:
40354
AN:
151776
Hom.:
5552
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.284
Gnomad AMI
AF:
0.353
Gnomad AMR
AF:
0.355
Gnomad ASJ
AF:
0.251
Gnomad EAS
AF:
0.298
Gnomad SAS
AF:
0.270
Gnomad FIN
AF:
0.218
Gnomad MID
AF:
0.206
Gnomad NFE
AF:
0.240
Gnomad OTH
AF:
0.262
GnomAD4 exome
AF:
0.248
AC:
184732
AN:
744596
Hom.:
23907
AF XY:
0.247
AC XY:
96656
AN XY:
390682
show subpopulations
African (AFR)
AF:
0.278
AC:
5195
AN:
18680
American (AMR)
AF:
0.402
AC:
14197
AN:
35310
Ashkenazi Jewish (ASJ)
AF:
0.254
AC:
5394
AN:
21274
East Asian (EAS)
AF:
0.255
AC:
8395
AN:
32880
South Asian (SAS)
AF:
0.265
AC:
17751
AN:
67080
European-Finnish (FIN)
AF:
0.208
AC:
8985
AN:
43224
Middle Eastern (MID)
AF:
0.239
AC:
1017
AN:
4252
European-Non Finnish (NFE)
AF:
0.235
AC:
114240
AN:
485260
Other (OTH)
AF:
0.261
AC:
9558
AN:
36636
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.489
Heterozygous variant carriers
0
7178
14357
21535
28714
35892
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2260
4520
6780
9040
11300
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.266
AC:
40387
AN:
151894
Hom.:
5559
Cov.:
31
AF XY:
0.267
AC XY:
19828
AN XY:
74262
show subpopulations
African (AFR)
AF:
0.283
AC:
11730
AN:
41398
American (AMR)
AF:
0.355
AC:
5419
AN:
15264
Ashkenazi Jewish (ASJ)
AF:
0.251
AC:
871
AN:
3468
East Asian (EAS)
AF:
0.298
AC:
1533
AN:
5148
South Asian (SAS)
AF:
0.270
AC:
1296
AN:
4808
European-Finnish (FIN)
AF:
0.218
AC:
2309
AN:
10580
Middle Eastern (MID)
AF:
0.207
AC:
61
AN:
294
European-Non Finnish (NFE)
AF:
0.240
AC:
16286
AN:
67918
Other (OTH)
AF:
0.266
AC:
561
AN:
2106
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.506
Heterozygous variant carriers
0
1510
3021
4531
6042
7552
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
408
816
1224
1632
2040
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.264
Hom.:
2076
Bravo
AF:
0.278
Asia WGS
AF:
0.309
AC:
1078
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

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
-0.85
CADD
Benign
0.095
DANN
Benign
0.69
PhyloP100
-1.9
Mutation Taster
=100/0
polymorphism (auto)

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

Publications

Other links and lift over

dbSNP: rs3212955; hg19: chr19-45923496; COSMIC: COSV50004094; COSMIC: COSV50004094; API