16-3606524-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032444.4(SLX4):c.710G>A(p.Arg237Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,614,176 control chromosomes in the GnomAD database, including 32 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R237W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0080 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 27 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.624

Publications

13 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=0.0029326975).

BP6

Variant 16-3606524-C-T is Benign according to our data. Variant chr16-3606524-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00797 (1213/152286) while in subpopulation AFR AF = 0.0167 (695/41544). AF 95% confidence interval is 0.0157. There are 5 homozygotes in GnomAd4. There are 588 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX4	NM_032444.4 link	c.710G>A	p.Arg237Gln	missense_variant	Exon 3 of 15	ENST00000294008.4	NP_115820.2	Q8IY92-1
SLX4	XM_024450471.2 link	c.710G>A	p.Arg237Gln	missense_variant	Exon 3 of 15		XP_024306239.1
SLX4	XM_011522715.4 link	c.710G>A	p.Arg237Gln	missense_variant	Exon 3 of 15		XP_011521017.1
SLX4	XR_007064923.1 link	n.1359G>A		non_coding_transcript_exon_variant	Exon 3 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLX4	ENST00000294008.4 link	c.710G>A	p.Arg237Gln	missense_variant	Exon 3 of 15	5	NM_032444.4	ENSP00000294008.3	Q8IY92-1
SLX4	ENST00000466154.5 link	n.1005G>A		non_coding_transcript_exon_variant	Exon 2 of 7	1
SLX4	ENST00000486524.1 link	n.1338G>A		non_coding_transcript_exon_variant	Exon 3 of 4	2
SLX4	ENST00000697858.1 link	n.51G>A		non_coding_transcript_exon_variant	Exon 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.00797

AC:

1213

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0168

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00426

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00810

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00516

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.00474

AC:

1189

AN:

251012

AF XY:

0.00436

show subpopulations

Gnomad AFR exome

AF:

0.0176

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0103

Gnomad NFE exome

AF:

0.00522

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00495

AC:

7237

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00473

AC XY:

3438

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0152

AC:

508

AN:

33478

American (AMR)

AF:

0.00203

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000574

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000128

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00874

AC:

467

AN:

53420

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00528

AC:

5873

AN:

1112010

Other (OTH)

AF:

0.00439

AC:

265

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

449

898

1348

1797

2246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

226

452

678

904

1130

<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:

0.00797

AC:

1213

AN:

152286

Hom.:

Cov.:

AF XY:

0.00790

AC XY:

588

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0167

AC:

695

AN:

41544

American (AMR)

AF:

0.00425

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00810

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00516

AC:

351

AN:

68034

Other (OTH)

AF:

0.00710

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

140

210

280

350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00571

Hom.:

Bravo

AF:

0.00832

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.0180

AC:

ESP6500EA

AF:

0.00477

AC:

ExAC

AF:

0.00505

AC:

613

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00425

EpiControl

AF:

0.00498

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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. -

Dec 07, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fanconi anemia complementation group P

Benign:3

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Feb 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 05, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

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 01, 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

0.084

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.019

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.014

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.22

MetaRNN

Benign

0.0029

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

PhyloP100

-0.62

PrimateAI

Benign

0.17

PROVEAN

Benign

0.24

REVEL

Benign

0.016

Sift

Benign

0.43

Sift4G

Benign

0.17

Polyphen

0.0

Vest4

0.086

MVP

0.081

MPC

0.062

ClinPred

0.00034

GERP RS

-10

Varity_R

0.013

gMVP

0.089

Mutation Taster

=98/2

polymorphism

(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