rs114472821

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032444.4(SLX4):c.2924C>T(p.Pro975Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,614,178 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P975P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0067 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 21 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.265

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=0.0032212734).

BP6

Variant 16-3590714-G-A is Benign according to our data. Variant chr16-3590714-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3590714-G-A is described in Lovd as [Benign]. Variant chr16-3590714-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00666 (1014/152342) while in subpopulation AFR AF= 0.0179 (744/41574). AF 95% confidence interval is 0.0168. There are 10 homozygotes in gnomad4. There are 489 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLX4	NM_032444.4 linkuse as main transcript	c.2924C>T	p.Pro975Leu	missense_variant	12/15	ENST00000294008.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLX4	ENST00000294008.4 linkuse as main transcript	c.2924C>T	p.Pro975Leu	missense_variant	12/15	5	NM_032444.4	P1	Q8IY92-1

Frequencies

GnomAD3 genomes

AF:

0.00663

AC:

1010

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0178

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00425

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00621

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00209

Gnomad OTH

AF:

0.00814

GnomAD3 exomes

AF:

0.00361

AC:

908

AN:

251262

Hom.:

AF XY:

0.00338

AC XY:

459

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.0168

Gnomad AMR exome

AF:

0.00431

Gnomad ASJ exome

AF:

0.00456

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00438

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00242

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00249

AC:

3636

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00258

AC XY:

1875

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0182

Gnomad4 AMR exome

AF:

0.00414

Gnomad4 ASJ exome

AF:

0.00402

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00543

Gnomad4 FIN exome

AF:

0.000394

Gnomad4 NFE exome

AF:

0.00170

Gnomad4 OTH exome

AF:

0.00407

GnomAD4 genome

AF:

0.00666

AC:

1014

AN:

152342

Hom.:

Cov.:

AF XY:

0.00656

AC XY:

489

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0179

Gnomad4 AMR

AF:

0.00425

Gnomad4 ASJ

AF:

0.00374

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00580

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00209

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.00311

Hom.:

Bravo

AF:

0.00704

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.0123

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00402

AC:

488

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00463

EpiControl

AF:

0.00362

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 31, 2012	Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 05, 2021	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Fanconi anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Fanconi anemia complementation group P

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.88

Cadd

Benign

1.1

Dann

Benign

0.31

DEOGEN2

Benign

0.012

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.39

MetaRNN

Benign

0.0032

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-0.20

MutationTaster

Benign

1.0

PrimateAI

Benign

0.19

PROVEAN

Benign

0.76

REVEL

Benign

0.054

Sift

Benign

1.0

Sift4G

Benign

0.53

Polyphen

0.0020

Vest4

0.061

MVP

0.072

MPC

0.056

ClinPred

0.00030

GERP RS

-4.3

Varity_R

0.0097

gMVP

0.080

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