rs141567438

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_032444.4(SLX4):c.4261A>T(p.Ile1421Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000948 in 1,590,344 control chromosomes in the GnomAD database, including 2 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 0.00063 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00098 ( 2 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: -2.41

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023132086).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000627 (95/151508) while in subpopulation NFE AF= 0.00108 (73/67818). AF 95% confidence interval is 0.000878. There are 0 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLX4	NM_032444.4 linkuse as main transcript	c.4261A>T	p.Ile1421Phe	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.4261A>T	p.Ile1421Phe	missense_variant	12/15	5	NM_032444.4	ENSP00000294008	P1	Q8IY92-1

Frequencies

GnomAD3 genomes

AF:

0.000628

AC:

AN:

151388

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000219

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000763

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00108

Gnomad OTH

AF:

0.000962

GnomAD3 exomes

AF:

0.000544

AC:

130

AN:

239028

Hom.:

AF XY:

0.000600

AC XY:

AN XY:

129996

show subpopulations

Gnomad AFR exome

AF:

0.000134

Gnomad AMR exome

AF:

0.0000902

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000393

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.00103

GnomAD4 exome

AF:

0.000981

AC:

1412

AN:

1438836

Hom.:

Cov.:

AF XY:

0.000907

AC XY:

646

AN XY:

712294

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.0000463

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.000527

Gnomad4 NFE exome

AF:

0.00122

Gnomad4 OTH exome

AF:

0.000624

GnomAD4 genome

AF:

0.000627

AC:

AN:

151508

Hom.:

Cov.:

AF XY:

0.000648

AC XY:

AN XY:

74054

show subpopulations

Gnomad4 AFR

AF:

0.000218

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000763

Gnomad4 NFE

AF:

0.00108

Gnomad4 OTH

AF:

0.000951

Alfa

AF:

0.00106

Hom.:

Bravo

AF:

0.000578

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000947

AC:

ExAC

AF:

0.000578

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2016	- -
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

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 02, 2018	- -
Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 31, 2012	Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker. -

Fanconi anemia

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Apr 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Fanconi anemia complementation group P

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 03, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.66

CADD

Benign

3.7

DANN

Benign

0.93

DEOGEN2

Benign

0.25

Eigen

Benign

-0.85

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.67

M_CAP

Benign

0.033

MetaRNN

Benign

0.023

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-2.1

REVEL

Benign

0.078

Sift

Uncertain

0.028

Sift4G

Uncertain

0.059

Polyphen

0.93

Vest4

0.22

MVP

0.085

MPC

0.18

ClinPred

0.034

GERP RS

-4.0

Varity_R

0.086

gMVP

0.27

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