16-3589581-G-T

Variant names:

Variant summary

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

The NM_032444.4(SLX4):c.4057C>A(p.His1353Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000683 in 1,613,234 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00071 ( 1 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 0.455

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:

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=0.02390632).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000407 (62/152190) while in subpopulation AMR AF= 0.000786 (12/15272). AF 95% confidence interval is 0.000508. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. 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 rank	MANE	Protein	UniProt
SLX4	NM_032444.4 link	c.4057C>A	p.His1353Asn	missense_variant	Exon 12 of 15	ENST00000294008.4	NP_115820.2	Q8IY92-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLX4	ENST00000294008.4 link	c.4057C>A	p.His1353Asn	missense_variant	Exon 12 of 15	5	NM_032444.4	ENSP00000294008.3		Q8IY92-1

Frequencies

GnomAD3 genomes

AF:

0.000407

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

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:

0.000661

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000367

AC:

AN:

250444

Hom.:

AF XY:

0.000347

AC XY:

AN XY:

135472

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000476

Gnomad NFE exome

AF:

0.000696

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000712

AC:

1040

AN:

1461044

Hom.:

Cov.:

AF XY:

0.000670

AC XY:

487

AN XY:

726814

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

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:

0.0000569

Gnomad4 NFE exome

AF:

0.000895

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.000407

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000786

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000661

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000679

Hom.:

Bravo

AF:

0.000446

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000338

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fanconi anemia complementation group P

Uncertain:4

Sep 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLX4 c.4057C>A; p.His1353Asn variant (rs142205392, ClinVar Variation ID: 241686), to our knowledge, has not been reported in individuals with bone marrow failure or related disorders. This variant is found predominantly in the non-Finnish European population with an allele frequency of 0.066% (85/128928 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is neutral (REVEL: 0.022). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Mar 17, 2021

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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. -

Apr 03, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:2

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or ovarian cancer (Sha 2013, Song 2020); This variant is associated with the following publications: (PMID: 23840564, 32546565) -

Fanconi anemia

Uncertain:1Benign:1

Oct 04, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Sep 01, 2021

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the SLX4 gene demonstrated a sequence change, c.4057C>A, in exon 12 that results in an amino acid change, p.His1353Asn. This sequence change does not appear to have been previously described in patients with SLX4-related disorders and has been described in the gnomAD database with a frequency of 0.07% in European populations (dbSNP rs142205392). The p.His1353Asn change affects a poorly conserved amino acid residue located in a domain of the SLX4 protein that is not known to be functional. The p.His1353Asn substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.His1353Asn change remains unknown at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.53

DANN

Benign

0.46

DEOGEN2

Benign

0.041

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.27

M_CAP

Benign

0.014

MetaRNN

Benign

0.024

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.69

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.1

REVEL

Benign

0.022

Sift

Benign

0.21

Sift4G

Benign

0.62

Polyphen

0.0010

Vest4

0.11

MVP

0.072

MPC

0.072

ClinPred

0.0033

GERP RS

-0.29

Varity_R

0.043

gMVP

0.10

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