rs74319927

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032444.4(SLX4):c.1371T>G(p.Asn457Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0631 in 1,612,600 control chromosomes in the GnomAD database, including 3,436 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.063 ( 319 hom., cov: 32)

Exomes 𝑓: 0.063 ( 3117 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.525

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

Fanconi anemia complementation group P
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SLX4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011074543).

BP6

Variant 16-3597691-A-C is Benign according to our data. Variant chr16-3597691-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 262035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX4	NM_032444.4 link	c.1371T>G	p.Asn457Lys	missense_variant	Exon 7 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.1371T>G	p.Asn457Lys	missense_variant	Exon 7 of 15	5	NM_032444.4	ENSP00000294008.3		Q8IY92-1
SLX4	ENST00000466154.5 link	n.2592T>G		non_coding_transcript_exon_variant	Exon 5 of 7	1

Frequencies

GnomAD3 genomes

AF:

0.0633

AC:

9616

AN:

151934

Hom.:

318

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0578

Gnomad AMI

AF:

0.0899

Gnomad AMR

AF:

0.0737

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.0365

Gnomad SAS

AF:

0.0538

Gnomad FIN

AF:

0.0868

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0656

Gnomad OTH

AF:

0.0574

GnomAD2 exomes

AF:

0.0617

AC:

15404

AN:

249510

AF XY:

0.0605

show subpopulations

Gnomad AFR exome

AF:

0.0571

Gnomad AMR exome

AF:

0.0716

Gnomad ASJ exome

AF:

0.0189

Gnomad EAS exome

AF:

0.0350

Gnomad FIN exome

AF:

0.0882

Gnomad NFE exome

AF:

0.0656

Gnomad OTH exome

AF:

0.0515

GnomAD4 exome

AF:

0.0630

AC:

92078

AN:

1460548

Hom.:

3117

Cov.:

AF XY:

0.0623

AC XY:

45293

AN XY:

726618

show subpopulations

African (AFR)

AF:

0.0580

AC:

1938

AN:

33436

American (AMR)

AF:

0.0685

AC:

3059

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.0189

AC:

494

AN:

26080

East Asian (EAS)

AF:

0.0316

AC:

1254

AN:

39636

South Asian (SAS)

AF:

0.0535

AC:

4618

AN:

86244

European-Finnish (FIN)

AF:

0.0834

AC:

4413

AN:

52902

Middle Eastern (MID)

AF:

0.0295

AC:

170

AN:

5766

European-Non Finnish (NFE)

AF:

0.0653

AC:

72550

AN:

1111488

Other (OTH)

AF:

0.0594

AC:

3582

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

5283

10565

15848

21130

26413

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0633

AC:

9625

AN:

152052

Hom.:

319

Cov.:

AF XY:

0.0644

AC XY:

4786

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.0579

AC:

2401

AN:

41448

American (AMR)

AF:

0.0735

AC:

1123

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

AN:

3470

East Asian (EAS)

AF:

0.0364

AC:

188

AN:

5162

South Asian (SAS)

AF:

0.0547

AC:

263

AN:

4812

European-Finnish (FIN)

AF:

0.0868

AC:

917

AN:

10562

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0656

AC:

4461

AN:

67992

Other (OTH)

AF:

0.0568

AC:

120

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

467

934

1401

1868

2335

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0622

Hom.:

131

Bravo

AF:

0.0626

TwinsUK

AF:

0.0612

AC:

227

ALSPAC

AF:

0.0620

AC:

239

ESP6500AA

AF:

0.0602

AC:

264

ESP6500EA

AF:

0.0676

AC:

581

ExAC

AF:

0.0625

AC:

7583

Asia WGS

AF:

0.0570

AC:

199

AN:

3478

EpiCase

AF:

0.0569

EpiControl

AF:

0.0586

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group P

Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 31, 2012

Leiden Open Variation Database

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker. -

not provided

Benign:2

Jan 22, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Fanconi anemia

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.051

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.18

MetaRNN

Benign

0.0011

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-2.3

PhyloP100

0.53

PrimateAI

Benign

0.43

PROVEAN

Benign

3.0

REVEL

Benign

0.18

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.058

MutPred

0.15

Gain of methylation at N457 (P = 0.0151);

MPC

0.062

ClinPred

0.0042

GERP RS

5.2

Varity_R

0.078

gMVP

0.079

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs74319927

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over