16-3582346-T-C

Position:

chr16-3582346-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_032444.4(SLX4):c.5501A>G(p.Asn1834Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00755 in 1,611,090 control chromosomes in the GnomAD database, including 45 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0056 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0077 ( 43 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 0.295

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050572455).

BP6

Variant 16-3582346-T-C is Benign according to our data. Variant chr16-3582346-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241697.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=1, Benign=3}. Variant chr16-3582346-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00564 (859/152336) while in subpopulation NFE AF= 0.0081 (551/68026). AF 95% confidence interval is 0.00754. There are 2 homozygotes in gnomad4. There are 407 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLX4	NM_032444.4 linkuse as main transcript	c.5501A>G	p.Asn1834Ser	missense_variant	15/15	ENST00000294008.4
SLX4	XM_024450471.2 linkuse as main transcript	c.5501A>G	p.Asn1834Ser	missense_variant	15/15
SLX4	XM_011522715.4 linkuse as main transcript	c.5498A>G	p.Asn1833Ser	missense_variant	15/15
SLX4	XM_047434801.1 linkuse as main transcript	c.4499A>G	p.Asn1500Ser	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4 linkuse as main transcript	c.5501A>G	p.Asn1834Ser	missense_variant	15/15	5	NM_032444.4	P1	Q8IY92-1
	ENST00000573982.1 linkuse as main transcript	n.199-790T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00564

AC:

859

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00169

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00641

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00988

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00810

Gnomad OTH

AF:

0.00573

GnomAD3 exomes

AF:

0.00558

AC:

1388

AN:

248708

Hom.:

AF XY:

0.00566

AC XY:

764

AN XY:

134906

show subpopulations

Gnomad AFR exome

AF:

0.00130

Gnomad AMR exome

AF:

0.00379

Gnomad ASJ exome

AF:

0.00467

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.00969

Gnomad NFE exome

AF:

0.00835

Gnomad OTH exome

AF:

0.00622

GnomAD4 exome

AF:

0.00775

AC:

11302

AN:

1458754

Hom.:

Cov.:

AF XY:

0.00754

AC XY:

5475

AN XY:

725810

show subpopulations

Gnomad4 AFR exome

AF:

0.00126

Gnomad4 AMR exome

AF:

0.00394

Gnomad4 ASJ exome

AF:

0.00436

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000557

Gnomad4 FIN exome

AF:

0.00884

Gnomad4 NFE exome

AF:

0.00903

Gnomad4 OTH exome

AF:

0.00656

GnomAD4 genome

AF:

0.00564

AC:

859

AN:

152336

Hom.:

Cov.:

AF XY:

0.00546

AC XY:

407

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00168

Gnomad4 AMR

AF:

0.00640

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00988

Gnomad4 NFE

AF:

0.00810

Gnomad4 OTH

AF:

0.00567

Alfa

AF:

0.00743

Hom.:

Bravo

AF:

0.00547

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00826

AC:

ExAC

AF:

0.00544

AC:

660

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00840

EpiControl

AF:

0.00865

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	SLX4: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 21, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2021	This variant is associated with the following publications: (PMID: 28051113, 28717660, 22401137, 28202063, 21805310) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 14, 2016	- -
Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 31, 2012	Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Apr 19, 2017	BS1,BP4,BP6; This alteration has an allele frequency that is greater than expected for the associated disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -

Fanconi anemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 02, 2021	- -

Fanconi anemia complementation group P

Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.68

CADD

Benign

2.2

DANN

Benign

0.82

DEOGEN2

Benign

0.014

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.48

M_CAP

Benign

0.045

MetaRNN

Benign

0.0051

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

0.10

REVEL

Benign

0.019

Sift

Benign

0.053

Sift4G

Pathogenic

0.0

Polyphen

0.0050

Vest4

0.089

MVP

0.12

MPC

0.048

ClinPred

0.0011

GERP RS

0.75

Varity_R

0.017

gMVP

0.21

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