rs373558741

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_032444.4(SLX4):​c.5477G>A​(p.Arg1826Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,613,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -2.05
Variant links:
Genes affected
SLX4 (HGNC:23845): (SLX4 structure-specific endonuclease subunit) This gene encodes a protein that functions as an assembly component of multiple structure-specific endonucleases. These endonuclease complexes are required for repair of specific types of DNA lesions and critical for cellular responses to replication fork failure. Mutations in this gene were found in patients with Fanconi anemia. [provided by RefSeq, Sep 2016]

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=0.008580208).
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000919 (14/152334) while in subpopulation SAS AF= 0.00103 (5/4832). AF 95% confidence interval is 0.000408. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLX4NM_032444.4 linkuse as main transcriptc.5477G>A p.Arg1826Gln missense_variant 15/15 ENST00000294008.4 NP_115820.2 Q8IY92-1
SLX4XM_024450471.2 linkuse as main transcriptc.5477G>A p.Arg1826Gln missense_variant 15/15 XP_024306239.1
SLX4XM_011522715.4 linkuse as main transcriptc.5474G>A p.Arg1825Gln missense_variant 15/15 XP_011521017.1
SLX4XM_047434801.1 linkuse as main transcriptc.4475G>A p.Arg1492Gln missense_variant 11/11 XP_047290757.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLX4ENST00000294008.4 linkuse as main transcriptc.5477G>A p.Arg1826Gln missense_variant 15/155 NM_032444.4 ENSP00000294008.3 Q8IY92-1
ENSG00000261938ENST00000573982.1 linkuse as main transcriptn.199-766C>T intron_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152216
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00103
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000920
AC:
23
AN:
249946
Hom.:
0
AF XY:
0.000133
AC XY:
18
AN XY:
135414
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000686
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000178
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000657
AC:
96
AN:
1460812
Hom.:
0
Cov.:
32
AF XY:
0.0000936
AC XY:
68
AN XY:
726736
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000673
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000270
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.0000919
AC:
14
AN:
152334
Hom.:
0
Cov.:
33
AF XY:
0.0000940
AC XY:
7
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00103
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000132
Hom.:
0
Bravo
AF:
0.0000680
ESP6500AA
AF:
0.000228
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000989
AC:
12
EpiCase
AF:
0.000218
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Fanconi anemia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 23, 2023This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1826 of the SLX4 protein (p.Arg1826Gln). This variant is present in population databases (rs373558741, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with SLX4-related conditions. ClinVar contains an entry for this variant (Variation ID: 407929). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Fanconi anemia complementation group P Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 30, 2022- -
SLX4-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 10, 2024The SLX4 c.5477G>A variant is predicted to result in the amino acid substitution p.Arg1826Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.069% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.099
BayesDel_addAF
Benign
-0.59
T
BayesDel_noAF
Benign
-0.72
CADD
Benign
0.027
DANN
Benign
0.89
DEOGEN2
Benign
0.032
T
Eigen
Benign
-1.9
Eigen_PC
Benign
-2.0
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.63
T
M_CAP
Benign
0.0069
T
MetaRNN
Benign
0.0086
T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
1.1
L
PrimateAI
Benign
0.21
T
PROVEAN
Benign
-0.51
N
REVEL
Benign
0.024
Sift
Benign
0.47
T
Sift4G
Benign
0.61
T
Polyphen
0.021
B
Vest4
0.11
MVP
0.048
MPC
0.064
ClinPred
0.034
T
GERP RS
-11
Varity_R
0.010
gMVP
0.25

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: rs373558741; hg19: chr16-3632371; COSMIC: COSV99036743; COSMIC: COSV99036743; API