16-3595606-A-G

Position:

chr16-3595606-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032444.4(SLX4):c.2012T>C(p.Leu671Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0645 in 1,613,608 control chromosomes in the GnomAD database, including 3,591 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.072 ( 408 hom., cov: 32)

Exomes 𝑓: 0.064 ( 3183 hom. )

Consequence

SLX4
NM_032444.4 missense, splice_region

Scores

Splicing: ADA: 0.00002109

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.591

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=0.0028672218).

BP6

Variant 16-3595606-A-G is Benign according to our data. Variant chr16-3595606-A-G is described in ClinVar as [Benign]. Clinvar id is 262040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3595606-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0868 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.2012T>C	p.Leu671Ser	missense_variant, splice_region_variant	9/15	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.2012T>C	p.Leu671Ser	missense_variant, splice_region_variant	9/15	5	NM_032444.4	ENSP00000294008	P1	Q8IY92-1
SLX4	ENST00000466154.5 linkuse as main transcript			downstream_gene_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0721

AC:

10971

AN:

152082

Hom.:

405

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0891

Gnomad AMI

AF:

0.0899

Gnomad AMR

AF:

0.0759

Gnomad ASJ

AF:

0.0188

Gnomad EAS

AF:

0.0365

Gnomad SAS

AF:

0.0536

Gnomad FIN

AF:

0.0867

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0656

Gnomad OTH

AF:

0.0669

GnomAD3 exomes

AF:

0.0636

AC:

15922

AN:

250160

Hom.:

589

AF XY:

0.0617

AC XY:

8352

AN XY:

135474

show subpopulations

Gnomad AFR exome

AF:

0.0894

Gnomad AMR exome

AF:

0.0725

Gnomad ASJ exome

AF:

0.0189

Gnomad EAS exome

AF:

0.0349

Gnomad SAS exome

AF:

0.0522

Gnomad FIN exome

AF:

0.0874

Gnomad NFE exome

AF:

0.0650

Gnomad OTH exome

AF:

0.0539

GnomAD4 exome

AF:

0.0637

AC:

93133

AN:

1461408

Hom.:

3183

Cov.:

AF XY:

0.0629

AC XY:

45760

AN XY:

727010

show subpopulations

Gnomad4 AFR exome

AF:

0.0862

Gnomad4 AMR exome

AF:

0.0698

Gnomad4 ASJ exome

AF:

0.0189

Gnomad4 EAS exome

AF:

0.0315

Gnomad4 SAS exome

AF:

0.0535

Gnomad4 FIN exome

AF:

0.0827

Gnomad4 NFE exome

AF:

0.0652

Gnomad4 OTH exome

AF:

0.0612

GnomAD4 genome

AF:

0.0722

AC:

10984

AN:

152200

Hom.:

408

Cov.:

AF XY:

0.0727

AC XY:

5409

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.0892

Gnomad4 AMR

AF:

0.0756

Gnomad4 ASJ

AF:

0.0188

Gnomad4 EAS

AF:

0.0364

Gnomad4 SAS

AF:

0.0545

Gnomad4 FIN

AF:

0.0867

Gnomad4 NFE

AF:

0.0656

Gnomad4 OTH

AF:

0.0662

Alfa

AF:

0.0629

Hom.:

211

Bravo

AF:

0.0731

TwinsUK

AF:

0.0599

AC:

222

ALSPAC

AF:

0.0620

AC:

239

ESP6500AA

AF:

0.0915

AC:

402

ESP6500EA

AF:

0.0677

AC:

582

ExAC

AF:

0.0654

AC:

7939

Asia WGS

AF:

0.0570

AC:

201

AN:

3478

EpiCase

AF:

0.0570

EpiControl

AF:

0.0586

ClinVar

Significance: Benign

Submissions summary: Benign:8

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:2

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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

0.065

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.82

CADD

Benign

8.3

DANN

Benign

0.19

DEOGEN2

Benign

0.018

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.00081

LIST_S2

Benign

0.10

MetaRNN

Benign

0.0029

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.2

MutationTaster

Benign

1.0

PrimateAI

Benign

0.36

PROVEAN

Benign

2.4

REVEL

Benign

0.044

Sift

Benign

0.59

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.076

MPC

0.073

ClinPred

0.00043

GERP RS

0.88

Varity_R

0.16

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000021

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.020

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