rs78637028

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.2855C>T(p.Ala952Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0602 in 1,613,928 control chromosomes in the GnomAD database, including 3,253 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. A952T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.050 ( 238 hom., cov: 33)

Exomes 𝑓: 0.061 ( 3015 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.432

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=0.0017929375).

BP6

Variant 16-3590783-G-A is Benign according to our data. Variant chr16-3590783-G-A is described in ClinVar as Benign. ClinVar VariationId is 262045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX4	NM_032444.4 link	c.2855C>T	p.Ala952Val	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.2855C>T	p.Ala952Val	missense_variant	Exon 12 of 15	5	NM_032444.4	ENSP00000294008.3		Q8IY92-1

Frequencies

GnomAD3 genomes

AF:

0.0498

AC:

7578

AN:

152150

Hom.:

238

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0118

Gnomad AMI

AF:

0.0899

Gnomad AMR

AF:

0.0691

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.0362

Gnomad SAS

AF:

0.0526

Gnomad FIN

AF:

0.0858

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0651

Gnomad OTH

AF:

0.0483

GnomAD2 exomes

AF:

0.0582

AC:

14609

AN:

251138

AF XY:

0.0578

show subpopulations

Gnomad AFR exome

AF:

0.0116

Gnomad AMR exome

AF:

0.0690

Gnomad ASJ exome

AF:

0.0189

Gnomad EAS exome

AF:

0.0355

Gnomad FIN exome

AF:

0.0881

Gnomad NFE exome

AF:

0.0651

Gnomad OTH exome

AF:

0.0502

GnomAD4 exome

AF:

0.0613

AC:

89633

AN:

1461660

Hom.:

3015

Cov.:

AF XY:

0.0609

AC XY:

44248

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.00914

AC:

306

AN:

33480

American (AMR)

AF:

0.0651

AC:

2909

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0189

AC:

494

AN:

26136

East Asian (EAS)

AF:

0.0317

AC:

1259

AN:

39700

South Asian (SAS)

AF:

0.0531

AC:

4581

AN:

86258

European-Finnish (FIN)

AF:

0.0829

AC:

4411

AN:

53210

Middle Eastern (MID)

AF:

0.0276

AC:

159

AN:

5768

European-Non Finnish (NFE)

AF:

0.0649

AC:

72179

AN:

1111996

Other (OTH)

AF:

0.0552

AC:

3335

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

5807

11614

17420

23227

29034

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2616

5232

7848

10464

13080

<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:

7575

AN:

152268

Hom.:

238

Cov.:

AF XY:

0.0513

AC XY:

3817

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0118

AC:

489

AN:

41566

American (AMR)

AF:

0.0688

AC:

1053

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

AN:

3472

East Asian (EAS)

AF:

0.0361

AC:

187

AN:

5180

South Asian (SAS)

AF:

0.0534

AC:

258

AN:

4828

European-Finnish (FIN)

AF:

0.0858

AC:

909

AN:

10598

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0651

AC:

4426

AN:

68000

Other (OTH)

AF:

0.0478

AC:

101

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

375

750

1126

1501

1876

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:

0.0563

Hom.:

610

Bravo

AF:

0.0465

TwinsUK

AF:

0.0599

AC:

222

ALSPAC

AF:

0.0612

AC:

236

ESP6500AA

AF:

0.0146

AC:

ESP6500EA

AF:

0.0647

AC:

556

ExAC

AF:

0.0583

AC:

7073

Asia WGS

AF:

0.0500

AC:

174

AN:

3478

EpiCase

AF:

0.0567

EpiControl

AF:

0.0583

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group P

Benign:2

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

- -

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 17, 2023

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

0.12

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.054

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.8

PhyloP100

-0.43

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.6

REVEL

Benign

0.027

Sift

Uncertain

0.019

Sift4G

Uncertain

0.045

Polyphen

0.93

Vest4

0.033

MPC

0.072

ClinPred

0.010

GERP RS

3.2

Varity_R

0.039

gMVP

0.15

Mutation Taster

=99/1

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