16-3590784-C-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.2854G>A(p.Ala952Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0653 in 1,613,960 control chromosomes in the GnomAD database, including 3,721 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. A952V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.077 ( 483 hom., cov: 32)

Exomes 𝑓: 0.064 ( 3238 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0130

Publications

14 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=0.0015773475).

BP6

Variant 16-3590784-C-T is Benign according to our data. Variant chr16-3590784-C-T is described in ClinVar as Benign. ClinVar VariationId is 262044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX4	NM_032444.4 link	c.2854G>A	p.Ala952Thr	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.2854G>A	p.Ala952Thr	missense_variant	Exon 12 of 15	5	NM_032444.4	ENSP00000294008.3

Frequencies

GnomAD3 genomes

AF:

0.0769

AC:

11706

AN:

152136

Hom.:

481

Cov.:

show subpopulations

Gnomad AFR

AF:

0.106

Gnomad AMI

AF:

0.0899

Gnomad AMR

AF:

0.0786

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.0362

Gnomad SAS

AF:

0.0532

Gnomad FIN

AF:

0.0859

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0653

Gnomad OTH

AF:

0.0684

GnomAD2 exomes

AF:

0.0652

AC:

16376

AN:

251170

AF XY:

0.0627

show subpopulations

Gnomad AFR exome

AF:

0.108

Gnomad AMR exome

AF:

0.0737

Gnomad ASJ exome

AF:

0.0189

Gnomad EAS exome

AF:

0.0355

Gnomad FIN exome

AF:

0.0881

Gnomad NFE exome

AF:

0.0652

Gnomad OTH exome

AF:

0.0532

GnomAD4 exome

AF:

0.0641

AC:

93676

AN:

1461706

Hom.:

3238

Cov.:

AF XY:

0.0632

AC XY:

45972

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.105

AC:

3518

AN:

33480

American (AMR)

AF:

0.0710

AC:

3173

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0189

AC:

494

AN:

26136

East Asian (EAS)

AF:

0.0317

AC:

1260

AN:

39700

South Asian (SAS)

AF:

0.0534

AC:

4610

AN:

86258

European-Finnish (FIN)

AF:

0.0829

AC:

4414

AN:

53254

Middle Eastern (MID)

AF:

0.0324

AC:

187

AN:

5768

European-Non Finnish (NFE)

AF:

0.0650

AC:

72271

AN:

1111996

Other (OTH)

AF:

0.0621

AC:

3749

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

6057

12115

18172

24230

30287

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2672

5344

8016

10688

13360

<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:

0.0770

AC:

11716

AN:

152254

Hom.:

483

Cov.:

AF XY:

0.0773

AC XY:

5758

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.106

AC:

4422

AN:

41532

American (AMR)

AF:

0.0783

AC:

1198

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

AN:

3472

East Asian (EAS)

AF:

0.0361

AC:

187

AN:

5182

South Asian (SAS)

AF:

0.0541

AC:

261

AN:

4824

European-Finnish (FIN)

AF:

0.0859

AC:

911

AN:

10606

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0653

AC:

4441

AN:

68016

Other (OTH)

AF:

0.0677

AC:

143

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

558

1115

1673

2230

2788

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

252

378

504

630

<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:

0.0530

Hom.:

162

Bravo

AF:

0.0787

TwinsUK

AF:

0.0599

AC:

222

ALSPAC

AF:

0.0607

AC:

234

ESP6500AA

AF:

0.108

AC:

476

ESP6500EA

AF:

0.0653

AC:

562

ExAC

AF:

0.0671

AC:

8147

Asia WGS

AF:

0.0550

AC:

193

AN:

3478

EpiCase

AF:

0.0569

EpiControl

AF:

0.0584

ClinVar

Significance: Benign

Submissions summary: Benign:7

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. -

Nov 27, 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 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

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fanconi anemia

Benign:1

Feb 02, 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

0.099

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.79

CADD

Benign

2.1

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.037

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.51

PhyloP100

0.013

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.64

REVEL

Benign

0.021

Sift

Benign

0.23

Sift4G

Benign

0.22

Polyphen

0.056

Vest4

0.025

MPC

0.083

ClinPred

0.0013

GERP RS

-1.4

Varity_R

0.029

gMVP

0.12

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