rs142008398

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_032444.4(SLX4):c.3676C>T(p.Arg1226Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,613,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 1.14

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]

SLX4 links:

SLX4 (HGNC:):

SLX4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0048915446).

BP6

Variant 16-3589962-G-A is Benign according to our data. Variant chr16-3589962-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 456313.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=3, Benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00103 (157/152064) while in subpopulation AFR AF= 0.00364 (151/41482). AF 95% confidence interval is 0.00317. There are 0 homozygotes in gnomad4. There are 68 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLX4	NM_032444.4 linkuse as main transcript	c.3676C>T	p.Arg1226Trp	missense_variant	12/15	ENST00000294008.4	NP_115820.2	Q8IY92-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLX4	ENST00000294008.4 linkuse as main transcript	c.3676C>T	p.Arg1226Trp	missense_variant	12/15	5	NM_032444.4	ENSP00000294008.3		Q8IY92-1

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

157

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00365

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000959

GnomAD3 exomes

AF:

0.000327

AC:

AN:

250660

Hom.:

AF XY:

0.000214

AC XY:

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.00442

Gnomad AMR exome

AF:

0.000202

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:

0.0000177

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000128

AC:

187

AN:

1461804

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00418

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.00103

AC:

157

AN:

152064

Hom.:

Cov.:

AF XY:

0.000915

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00364

Gnomad4 AMR

AF:

0.000262

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:

0.000949

Alfa

AF:

0.000175

Hom.:

Bravo

AF:

0.00109

ESP6500AA

AF:

0.00432

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000379

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fanconi anemia

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 18, 2021	- -

Fanconi anemia complementation group P

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 13, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 08, 2022

DNA sequence analysis of the SLX4 gene demonstrated a sequence change, c.3676C>T, in exon 12 that results in an amino acid change, p.Arg1226Trp. This sequence change has been previously described in familial breast cancer cases (PMID: 23840564). This sequence change has been described in the gnomAD database with a frequency of 0.4% in the African/African American subpopulation (dbSNP rs142008398). The p.Arg1226Trp change affects a poorly conserved amino acid residue located in a domain of the SLX4 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg1226Trp substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg1226Trp change remains unknown at this time. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 25, 2021

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -

SLX4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 18, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.55

M_CAP

Benign

0.038

MetaRNN

Benign

0.0049

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.19

PROVEAN

Benign

-2.3

REVEL

Benign

0.055

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.012

Polyphen

0.99

Vest4

0.20

MVP

0.24

MPC

0.21

ClinPred

0.023

GERP RS

0.24

Varity_R

0.065

gMVP

0.15

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over