NM_032444.4:c.3662C>T

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.3662C>T(p.Ala1221Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0603 in 1,613,786 control chromosomes in the GnomAD database, including 3,256 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1221L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.050 ( 241 hom., cov: 32)

Exomes 𝑓: 0.061 ( 3015 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.330

Publications

25 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=0.0017294586).

BP6

Variant 16-3589976-G-A is Benign according to our data. Variant chr16-3589976-G-A is described in ClinVar as Benign. ClinVar VariationId is 262048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX4	NM_032444.4 link	c.3662C>T	p.Ala1221Val	missense_variant	Exon 12 of 15	ENST00000294008.4	NP_115820.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLX4	ENST00000294008.4 link	c.3662C>T	p.Ala1221Val	missense_variant	Exon 12 of 15	5	NM_032444.4	ENSP00000294008.3

Frequencies

GnomAD3 genomes

AF:

0.0498

AC:

7559

AN:

151906

Hom.:

241

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0118

Gnomad AMI

AF:

0.0899

Gnomad AMR

AF:

0.0689

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.0356

Gnomad SAS

AF:

0.0521

Gnomad FIN

AF:

0.0859

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0651

Gnomad OTH

AF:

0.0473

GnomAD2 exomes

AF:

0.0583

AC:

14614

AN:

250722

AF XY:

0.0579

show subpopulations

Gnomad AFR exome

AF:

0.0115

Gnomad AMR exome

AF:

0.0690

Gnomad ASJ exome

AF:

0.0189

Gnomad EAS exome

AF:

0.0354

Gnomad FIN exome

AF:

0.0883

Gnomad NFE exome

AF:

0.0653

Gnomad OTH exome

AF:

0.0503

GnomAD4 exome

AF:

0.0614

AC:

89737

AN:

1461762

Hom.:

3015

Cov.:

AF XY:

0.0609

AC XY:

44295

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00920

AC:

308

AN:

33480

American (AMR)

AF:

0.0651

AC:

2912

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0189

AC:

494

AN:

26136

East Asian (EAS)

AF:

0.0317

AC:

1257

AN:

39700

South Asian (SAS)

AF:

0.0532

AC:

4591

AN:

86258

European-Finnish (FIN)

AF:

0.0830

AC:

4421

AN:

53294

Middle Eastern (MID)

AF:

0.0276

AC:

159

AN:

5768

European-Non Finnish (NFE)

AF:

0.0650

AC:

72256

AN:

1112008

Other (OTH)

AF:

0.0553

AC:

3339

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

6074

12149

18223

24298

30372

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2618

5236

7854

10472

13090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0497

AC:

7556

AN:

152024

Hom.:

241

Cov.:

AF XY:

0.0512

AC XY:

3805

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0117

AC:

486

AN:

41464

American (AMR)

AF:

0.0686

AC:

1048

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

AN:

3472

East Asian (EAS)

AF:

0.0355

AC:

183

AN:

5158

South Asian (SAS)

AF:

0.0530

AC:

254

AN:

4792

European-Finnish (FIN)

AF:

0.0859

AC:

909

AN:

10580

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0651

AC:

4425

AN:

67972

Other (OTH)

AF:

0.0468

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

349

697

1046

1394

1743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

270

360

450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0572

Hom.:

293

Bravo

AF:

0.0464

TwinsUK

AF:

0.0612

AC:

227

ALSPAC

AF:

0.0612

AC:

236

ESP6500AA

AF:

0.0148

AC:

ESP6500EA

AF:

0.0669

AC:

575

ExAC

AF:

0.0583

AC:

7078

Asia WGS

AF:

0.0500

AC:

175

AN:

3478

EpiCase

AF:

0.0567

EpiControl

AF:

0.0583

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group P

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Aug 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 24, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: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

0.081

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.83

CADD

Benign

3.2

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.016

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PhyloP100

-0.33

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.17

REVEL

Benign

0.0030

Sift

Benign

0.30

Sift4G

Benign

0.34

Polyphen

0.019

Vest4

0.015

MPC

0.056

ClinPred

0.00066

GERP RS

-3.8

Varity_R

0.024

gMVP

0.084

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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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