rs3810813

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.3812C>T(p.Ser1271Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0597 in 1,613,372 control chromosomes in the GnomAD database, including 3,590 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.050 ( 280 hom., cov: 32)

Exomes 𝑓: 0.061 ( 3310 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.04

Publications

41 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=0.0015541315).

BP6

Variant 16-3589826-G-A is Benign according to our data. Variant chr16-3589826-G-A is described in ClinVar as Benign. ClinVar VariationId is 262050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX4	NM_032444.4 link	c.3812C>T	p.Ser1271Phe	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.3812C>T	p.Ser1271Phe	missense_variant	Exon 12 of 15	5	NM_032444.4	ENSP00000294008.3		Q8IY92-1

Frequencies

GnomAD3 genomes

AF:

0.0498

AC:

7569

AN:

152140

Hom.:

276

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0110

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0573

Gnomad ASJ

AF:

0.0317

Gnomad EAS

AF:

0.177

Gnomad SAS

AF:

0.0684

Gnomad FIN

AF:

0.0704

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0586

Gnomad OTH

AF:

0.0479

GnomAD2 exomes

AF:

0.0662

AC:

16583

AN:

250642

AF XY:

0.0659

show subpopulations

Gnomad AFR exome

AF:

0.00981

Gnomad AMR exome

AF:

0.0801

Gnomad ASJ exome

AF:

0.0355

Gnomad EAS exome

AF:

0.185

Gnomad FIN exome

AF:

0.0659

Gnomad NFE exome

AF:

0.0540

Gnomad OTH exome

AF:

0.0576

GnomAD4 exome

AF:

0.0607

AC:

88747

AN:

1461114

Hom.:

3310

Cov.:

AF XY:

0.0611

AC XY:

44390

AN XY:

726896

show subpopulations

African (AFR)

AF:

0.00860

AC:

288

AN:

33480

American (AMR)

AF:

0.0761

AC:

3405

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0354

AC:

925

AN:

26136

East Asian (EAS)

AF:

0.198

AC:

7846

AN:

39700

South Asian (SAS)

AF:

0.0653

AC:

5633

AN:

86258

European-Finnish (FIN)

AF:

0.0647

AC:

3406

AN:

52648

Middle Eastern (MID)

AF:

0.0479

AC:

276

AN:

5768

European-Non Finnish (NFE)

AF:

0.0569

AC:

63235

AN:

1112004

Other (OTH)

AF:

0.0618

AC:

3733

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

5992

11983

17975

23966

29958

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2460

4920

7380

9840

12300

<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:

0.0498

AC:

7577

AN:

152258

Hom.:

280

Cov.:

AF XY:

0.0510

AC XY:

3797

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0110

AC:

457

AN:

41546

American (AMR)

AF:

0.0579

AC:

886

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0317

AC:

110

AN:

3470

East Asian (EAS)

AF:

0.177

AC:

915

AN:

5168

South Asian (SAS)

AF:

0.0680

AC:

328

AN:

4824

European-Finnish (FIN)

AF:

0.0704

AC:

747

AN:

10616

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0586

AC:

3983

AN:

68022

Other (OTH)

AF:

0.0498

AC:

105

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

365

730

1094

1459

1824

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<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:

0.0570

Hom.:

1370

Bravo

AF:

0.0491

TwinsUK

AF:

0.0620

AC:

230

ALSPAC

AF:

0.0597

AC:

230

ESP6500AA

AF:

0.0132

AC:

ESP6500EA

AF:

0.0545

AC:

469

ExAC

AF:

0.0641

AC:

7783

Asia WGS

AF:

0.118

AC:

408

AN:

3478

EpiCase

AF:

0.0585

EpiControl

AF:

0.0551

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. -

Oct 30, 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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 24, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.20

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

4.0

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.11

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.16

MPC

0.37

ClinPred

0.013

GERP RS

5.1

Varity_R

0.27

gMVP

0.42

Mutation Taster

=92/8

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