rs138615800

Variant summary

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

The NM_032444.4(SLX4):​c.710G>A​(p.Arg237Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,614,176 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0080 ( 5 hom., cov: 32)
Exomes 𝑓: 0.0050 ( 27 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

18

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.624
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0029326975).
BP6
Variant 16-3606524-C-T is Benign according to our data. Variant chr16-3606524-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 212222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3606524-C-T is described in Lovd as [Benign]. Variant chr16-3606524-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00797 (1213/152286) while in subpopulation AFR AF= 0.0167 (695/41544). AF 95% confidence interval is 0.0157. There are 5 homozygotes in gnomad4. There are 588 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
SLX4NM_032444.4 linkuse as main transcriptc.710G>A p.Arg237Gln missense_variant 3/15 ENST00000294008.4 NP_115820.2
SLX4XM_024450471.2 linkuse as main transcriptc.710G>A p.Arg237Gln missense_variant 3/15 XP_024306239.1
SLX4XM_011522715.4 linkuse as main transcriptc.710G>A p.Arg237Gln missense_variant 3/15 XP_011521017.1
SLX4XR_007064923.1 linkuse as main transcriptn.1359G>A non_coding_transcript_exon_variant 3/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLX4ENST00000294008.4 linkuse as main transcriptc.710G>A p.Arg237Gln missense_variant 3/155 NM_032444.4 ENSP00000294008 P1Q8IY92-1
SLX4ENST00000466154.5 linkuse as main transcriptn.1005G>A non_coding_transcript_exon_variant 2/71
SLX4ENST00000486524.1 linkuse as main transcriptn.1338G>A non_coding_transcript_exon_variant 3/42
SLX4ENST00000697858.1 linkuse as main transcriptn.51G>A non_coding_transcript_exon_variant 1/3

Frequencies

GnomAD3 genomes
AF:
0.00797
AC:
1213
AN:
152170
Hom.:
5
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0168
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00426
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00810
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00516
Gnomad OTH
AF:
0.00718
GnomAD3 exomes
AF:
0.00474
AC:
1189
AN:
251012
Hom.:
8
AF XY:
0.00436
AC XY:
591
AN XY:
135702
show subpopulations
Gnomad AFR exome
AF:
0.0176
Gnomad AMR exome
AF:
0.00171
Gnomad ASJ exome
AF:
0.000298
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.0103
Gnomad NFE exome
AF:
0.00522
Gnomad OTH exome
AF:
0.00391
GnomAD4 exome
AF:
0.00495
AC:
7237
AN:
1461890
Hom.:
27
Cov.:
33
AF XY:
0.00473
AC XY:
3438
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0152
Gnomad4 AMR exome
AF:
0.00203
Gnomad4 ASJ exome
AF:
0.000574
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000128
Gnomad4 FIN exome
AF:
0.00874
Gnomad4 NFE exome
AF:
0.00528
Gnomad4 OTH exome
AF:
0.00439
GnomAD4 genome
AF:
0.00797
AC:
1213
AN:
152286
Hom.:
5
Cov.:
32
AF XY:
0.00790
AC XY:
588
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.0167
Gnomad4 AMR
AF:
0.00425
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00810
Gnomad4 NFE
AF:
0.00516
Gnomad4 OTH
AF:
0.00710
Alfa
AF:
0.00515
Hom.:
8
Bravo
AF:
0.00832
TwinsUK
AF:
0.00431
AC:
16
ALSPAC
AF:
0.00467
AC:
18
ESP6500AA
AF:
0.0180
AC:
79
ESP6500EA
AF:
0.00477
AC:
41
ExAC
AF:
0.00505
AC:
613
Asia WGS
AF:
0.00173
AC:
6
AN:
3478
EpiCase
AF:
0.00425
EpiControl
AF:
0.00498

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Likely benign, no assertion criteria providedcurationLeiden Open Variation DatabaseAug 31, 2012Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker. -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoDec 07, 2016- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Fanconi anemia complementation group P Benign:2
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. -
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJan 05, 2017- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Fanconi anemia Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.084
BayesDel_addAF
Benign
-0.76
T
BayesDel_noAF
Benign
-0.86
CADD
Benign
0.019
DANN
Benign
0.76
DEOGEN2
Benign
0.014
T
Eigen
Benign
-2.3
Eigen_PC
Benign
-2.4
FATHMM_MKL
Benign
0.015
N
LIST_S2
Benign
0.22
T
MetaRNN
Benign
0.0029
T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
0.0
N
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.17
T
PROVEAN
Benign
0.24
N
REVEL
Benign
0.016
Sift
Benign
0.43
T
Sift4G
Benign
0.17
T
Polyphen
0.0
B
Vest4
0.086
MVP
0.081
MPC
0.062
ClinPred
0.00034
T
GERP RS
-10
Varity_R
0.013
gMVP
0.089

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: rs138615800; hg19: chr16-3656525; API