rs148791570

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_005236.3(ERCC4):​c.325G>A​(p.Ala109Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,613,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A109V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00096 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

ERCC4
NM_005236.3 missense

Scores

7
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 9.49
Variant links:
Genes affected
ERCC4 (HGNC:3436): (ERCC excision repair 4, endonuclease catalytic subunit) The protein encoded by this gene forms a complex with ERCC1 and is involved in the 5' incision made during nucleotide excision repair. This complex is a structure specific DNA repair endonuclease that interacts with EME1. Defects in this gene are a cause of xeroderma pigmentosum complementation group F (XP-F), or xeroderma pigmentosum VI (XP6).[provided by RefSeq, Mar 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.018114).
BP6
Variant 16-13922148-G-A is Benign according to our data. Variant chr16-13922148-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 474205.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ERCC4NM_005236.3 linkuse as main transcriptc.325G>A p.Ala109Thr missense_variant 2/11 ENST00000311895.8
LOC105371093XR_007065000.1 linkuse as main transcriptn.82+4377C>T intron_variant, non_coding_transcript_variant
ERCC4XM_011522424.4 linkuse as main transcriptc.325G>A p.Ala109Thr missense_variant 2/12
LOC105371093XR_007064999.1 linkuse as main transcriptn.82+4377C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ERCC4ENST00000311895.8 linkuse as main transcriptc.325G>A p.Ala109Thr missense_variant 2/111 NM_005236.3 P1Q92889-1

Frequencies

GnomAD3 genomes
AF:
0.000959
AC:
146
AN:
152164
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00331
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.000267
AC:
67
AN:
251316
Hom.:
0
AF XY:
0.000191
AC XY:
26
AN XY:
135856
show subpopulations
Gnomad AFR exome
AF:
0.00351
Gnomad AMR exome
AF:
0.000231
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.0000958
AC:
140
AN:
1460964
Hom.:
0
Cov.:
30
AF XY:
0.0000922
AC XY:
67
AN XY:
726846
show subpopulations
Gnomad4 AFR exome
AF:
0.00338
Gnomad4 AMR exome
AF:
0.000268
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.000232
GnomAD4 genome
AF:
0.000959
AC:
146
AN:
152282
Hom.:
0
Cov.:
32
AF XY:
0.000859
AC XY:
64
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.00330
Gnomad4 AMR
AF:
0.000457
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.000236
Hom.:
0
Bravo
AF:
0.00126
ESP6500AA
AF:
0.00250
AC:
11
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000321
AC:
39
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Xeroderma pigmentosum Uncertain:1
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Aug 13, 2021- -
Xeroderma pigmentosum, group F Uncertain:1
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoDec 22, 2020- -
Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 26, 2023- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxFeb 22, 2021This variant is associated with the following publications: (PMID: 28767289) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.23
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.44
.;T
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.018
T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
1.5
L;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-0.42
.;N
REVEL
Benign
0.20
Sift
Benign
0.045
.;D
Sift4G
Benign
0.10
T;D
Polyphen
0.081
.;B
Vest4
0.56
MVP
0.87
MPC
0.11
ClinPred
0.034
T
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.30
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs148791570; hg19: chr16-14016005; API