rs116781836

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_032444.4(SLX4):c.3963G>A(p.Pro1321Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00605 in 1,613,938 control chromosomes in the GnomAD database, including 144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0088 ( 15 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 129 hom. )

Consequence

SLX4
NM_032444.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.936

Publications

4 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 16-3589675-C-T is Benign according to our data. Variant chr16-3589675-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.936 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00883 (1344/152242) while in subpopulation SAS AF = 0.0448 (216/4820). AF 95% confidence interval is 0.0399. There are 15 homozygotes in GnomAd4. There are 687 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX4	NM_032444.4 link	c.3963G>A	p.Pro1321Pro	synonymous_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.3963G>A	p.Pro1321Pro	synonymous_variant	Exon 12 of 15	5	NM_032444.4	ENSP00000294008.3		Q8IY92-1

Frequencies

GnomAD3 genomes

AF:

0.00882

AC:

1342

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00505

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0456

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00325

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00916

AC:

2301

AN:

251260

AF XY:

0.0107

show subpopulations

Gnomad AFR exome

AF:

0.0169

Gnomad AMR exome

AF:

0.00477

Gnomad ASJ exome

AF:

0.0135

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.000187

Gnomad NFE exome

AF:

0.00357

Gnomad OTH exome

AF:

0.00863

GnomAD4 exome

AF:

0.00576

AC:

8416

AN:

1461696

Hom.:

129

Cov.:

AF XY:

0.00694

AC XY:

5044

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.0182

AC:

609

AN:

33480

American (AMR)

AF:

0.00456

AC:

204

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0117

AC:

307

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0439

AC:

3785

AN:

86258

European-Finnish (FIN)

AF:

0.000413

AC:

AN:

53258

Middle Eastern (MID)

AF:

0.0324

AC:

187

AN:

5768

European-Non Finnish (NFE)

AF:

0.00255

AC:

2834

AN:

1111992

Other (OTH)

AF:

0.00767

AC:

463

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

591

1182

1774

2365

2956

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

280

420

560

700

<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:

0.00883

AC:

1344

AN:

152242

Hom.:

Cov.:

AF XY:

0.00923

AC XY:

687

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0180

AC:

749

AN:

41542

American (AMR)

AF:

0.00504

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.0448

AC:

216

AN:

4820

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00325

AC:

221

AN:

68026

Other (OTH)

AF:

0.0109

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

134

200

267

334

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00708

Hom.:

Bravo

AF:

0.00826

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.00600

EpiControl

AF:

0.00533

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

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. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

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

Oct 26, 2021

GeneDx

Significance:Likely 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 03, 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

BayesDel_noAF

Benign

-0.68

CADD

Benign

2.9

(source)

DANN

Benign

0.54

PhyloP100

-0.94

Mutation Taster

=100/0

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