chr16-3590273-G-A

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.3365C>T(p.Pro1122Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,613,854 control chromosomes in the GnomAD database, including 15,972 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. P1122A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.20 ( 5242 hom., cov: 32)

Exomes 𝑓: 0.10 ( 10730 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.123

Publications

46 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=2.5084615E-4).

BP6

Variant 16-3590273-G-A is Benign according to our data. Variant chr16-3590273-G-A is described in ClinVar as Benign. ClinVar VariationId is 262047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032444.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	NM_032444.4	MANE Select	c.3365C>T	p.Pro1122Leu	missense	Exon 12 of 15	NP_115820.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	ENST00000294008.4	TSL:5 MANE Select	c.3365C>T	p.Pro1122Leu	missense	Exon 12 of 15	ENSP00000294008.3

Frequencies

GnomAD3 genomes

AF:

0.200

AC:

30309

AN:

151868

Hom.:

5215

Cov.:

show subpopulations

Gnomad AFR

AF:

0.470

Gnomad AMI

AF:

0.111

Gnomad AMR

AF:

0.146

Gnomad ASJ

AF:

0.0597

Gnomad EAS

AF:

0.0865

Gnomad SAS

AF:

0.185

Gnomad FIN

AF:

0.100

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0815

Gnomad OTH

AF:

0.178

GnomAD2 exomes

AF:

0.125

AC:

31500

AN:

251384

AF XY:

0.121

show subpopulations

Gnomad AFR exome

AF:

0.481

Gnomad AMR exome

AF:

0.111

Gnomad ASJ exome

AF:

0.0556

Gnomad EAS exome

AF:

0.0883

Gnomad FIN exome

AF:

0.103

Gnomad NFE exome

AF:

0.0822

Gnomad OTH exome

AF:

0.0984

GnomAD4 exome

AF:

0.0999

AC:

146005

AN:

1461868

Hom.:

10730

Cov.:

AF XY:

0.101

AC XY:

73266

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.500

AC:

16755

AN:

33480

American (AMR)

AF:

0.110

AC:

4903

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0550

AC:

1438

AN:

26136

East Asian (EAS)

AF:

0.0905

AC:

3593

AN:

39700

South Asian (SAS)

AF:

0.180

AC:

15562

AN:

86258

European-Finnish (FIN)

AF:

0.0967

AC:

5162

AN:

53398

Middle Eastern (MID)

AF:

0.124

AC:

714

AN:

5768

European-Non Finnish (NFE)

AF:

0.0815

AC:

90664

AN:

1112008

Other (OTH)

AF:

0.119

AC:

7214

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

8931

17861

26792

35722

44653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3608

7216

10824

14432

18040

<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:

0.200

AC:

30379

AN:

151986

Hom.:

5242

Cov.:

AF XY:

0.200

AC XY:

14831

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.471

AC:

19514

AN:

41426

American (AMR)

AF:

0.145

AC:

2223

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0597

AC:

207

AN:

3470

East Asian (EAS)

AF:

0.0867

AC:

446

AN:

5142

South Asian (SAS)

AF:

0.185

AC:

889

AN:

4816

European-Finnish (FIN)

AF:

0.100

AC:

1059

AN:

10572

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0815

AC:

5537

AN:

67962

Other (OTH)

AF:

0.175

AC:

370

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1004

2007

3011

4014

5018

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

286

572

858

1144

1430

<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:

0.125

Hom.:

7167

Bravo

AF:

0.215

TwinsUK

AF:

0.0787

AC:

292

ALSPAC

AF:

0.0786

AC:

303

ESP6500AA

AF:

0.461

AC:

2027

ESP6500EA

AF:

0.0841

AC:

723

ExAC

AF:

0.135

AC:

16360

Asia WGS

AF:

0.175

AC:

610

AN:

3478

EpiCase

AF:

0.0804

EpiControl

AF:

0.0819

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group P

Benign:4

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 18, 2017

IntelligeneCG

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 12, 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.

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 25, 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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.83

CADD

Benign

8.2

(source)

DANN

Benign

0.20

DEOGEN2

Benign

0.24

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.22

MetaRNN

Benign

0.00025

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.14

PhyloP100

0.12

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.028

Sift

Benign

0.82

Sift4G

Benign

0.23

Polyphen

0.0030

Vest4

0.013

MPC

0.057

ClinPred

0.0068

GERP RS

-0.66

Varity_R

0.038

gMVP

0.11

Mutation Taster

=97/3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over