rs714181

Positions:

chr16-3590273-G-A

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 262047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3590273-G-A is described in Lovd as [Likely_benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLX4	NM_032444.4 linkuse as main transcript	c.3365C>T	p.Pro1122Leu	missense_variant	12/15	ENST00000294008.4	NP_115820.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLX4	ENST00000294008.4 linkuse as main transcript	c.3365C>T	p.Pro1122Leu	missense_variant	12/15	5	NM_032444.4	ENSP00000294008	P1	Q8IY92-1

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

GnomAD3 exomes

AF:

0.125

AC:

31500

AN:

251384

Hom.:

3261

AF XY:

0.121

AC XY:

16439

AN XY:

135870

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 SAS exome

AF:

0.180

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

Gnomad4 AFR exome

AF:

0.500

Gnomad4 AMR exome

AF:

0.110

Gnomad4 ASJ exome

AF:

0.0550

Gnomad4 EAS exome

AF:

0.0905

Gnomad4 SAS exome

AF:

0.180

Gnomad4 FIN exome

AF:

0.0967

Gnomad4 NFE exome

AF:

0.0815

Gnomad4 OTH exome

AF:

0.119

GnomAD4 genome

AF:

0.200

AC:

30379

AN:

151986

Hom.:

5242

Cov.:

AF XY:

0.200

AC XY:

14831

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.471

Gnomad4 AMR

AF:

0.145

Gnomad4 ASJ

AF:

0.0597

Gnomad4 EAS

AF:

0.0867

Gnomad4 SAS

AF:

0.185

Gnomad4 FIN

AF:

0.100

Gnomad4 NFE

AF:

0.0815

Gnomad4 OTH

AF:

0.175

Alfa

AF:

0.104

Hom.:

3148

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

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2016	- -
Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 31, 2012	Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Fanconi anemia complementation group P

Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	IntelligeneCG	Aug 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2019	- -

Fanconi anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.83

CADD

Benign

8.2

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

MutationTaster

Benign

1.0

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over