2-127257567-G-A

Variant summary

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

The NM_000122.2(ERCC3):​c.*29C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,612,784 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0070 ( 5 hom., cov: 32)
Exomes 𝑓: 0.011 ( 104 hom. )

Consequence

ERCC3
NM_000122.2 3_prime_UTR

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.347
Variant links:
Genes affected
ERCC3 (HGNC:3435): (ERCC excision repair 3, TFIIH core complex helicase subunit) This gene encodes an ATP-dependent DNA helicase that functions in nucleotide excision repair. The encoded protein is a subunit of basal transcription factor 2 (TFIIH) and, therefore, also functions in class II transcription. Mutations in this gene are associated with Xeroderma pigmentosum B, Cockayne's syndrome, and trichothiodystrophy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

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 (BayesDel_noAF=-0.9).
BP6
Variant 2-127257567-G-A is Benign according to our data. Variant chr2-127257567-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 331072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00702 (1069/152274) while in subpopulation NFE AF= 0.012 (816/68022). AF 95% confidence interval is 0.0113. There are 5 homozygotes in gnomad4. There are 496 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ERCC3NM_000122.2 linkuse as main transcriptc.*29C>T 3_prime_UTR_variant 15/15 ENST00000285398.7 NP_000113.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ERCC3ENST00000285398.7 linkuse as main transcriptc.*29C>T 3_prime_UTR_variant 15/151 NM_000122.2 ENSP00000285398 P1

Frequencies

GnomAD3 genomes
AF:
0.00703
AC:
1069
AN:
152156
Hom.:
5
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00222
Gnomad AMI
AF:
0.00658
Gnomad AMR
AF:
0.00504
Gnomad ASJ
AF:
0.00202
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00424
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.0120
Gnomad OTH
AF:
0.00956
GnomAD3 exomes
AF:
0.00680
AC:
1709
AN:
251422
Hom.:
10
AF XY:
0.00674
AC XY:
916
AN XY:
135872
show subpopulations
Gnomad AFR exome
AF:
0.00185
Gnomad AMR exome
AF:
0.00335
Gnomad ASJ exome
AF:
0.00308
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000457
Gnomad FIN exome
AF:
0.00397
Gnomad NFE exome
AF:
0.0124
Gnomad OTH exome
AF:
0.00440
GnomAD4 exome
AF:
0.0110
AC:
16017
AN:
1460510
Hom.:
104
Cov.:
31
AF XY:
0.0106
AC XY:
7720
AN XY:
726560
show subpopulations
Gnomad4 AFR exome
AF:
0.00224
Gnomad4 AMR exome
AF:
0.00338
Gnomad4 ASJ exome
AF:
0.00356
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000603
Gnomad4 FIN exome
AF:
0.00433
Gnomad4 NFE exome
AF:
0.0134
Gnomad4 OTH exome
AF:
0.00849
GnomAD4 genome
AF:
0.00702
AC:
1069
AN:
152274
Hom.:
5
Cov.:
32
AF XY:
0.00666
AC XY:
496
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.00221
Gnomad4 AMR
AF:
0.00503
Gnomad4 ASJ
AF:
0.00202
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00424
Gnomad4 NFE
AF:
0.0120
Gnomad4 OTH
AF:
0.00946
Alfa
AF:
0.0105
Hom.:
7
Bravo
AF:
0.00696
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2023ERCC3: BS1, BS2 -
Likely benign, criteria provided, single submitterclinical testingGeneDxApr 04, 2019- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Xeroderma pigmentosum group B Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
4.4
DANN
Benign
0.64
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0

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

LitVar

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

Other links and lift over

dbSNP: rs4150523; hg19: chr2-128015143; COSMIC: COSV53430625; COSMIC: COSV53430625; API