16-3591279-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_032444.4(SLX4):c.2359G>A(p.Glu787Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,612,302 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E787G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 3 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:6

Conservation

PhyloP100: 0.345

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 was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017253429).

BP6

Variant 16-3591279-C-T is Benign according to our data. Variant chr16-3591279-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 407938.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=3, Benign=1}. Variant chr16-3591279-C-T is described in Lovd as [Likely_benign]. Variant chr16-3591279-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00121 (185/152304) while in subpopulation NFE AF = 0.0016 (109/68030). AF 95% confidence interval is 0.00136. There are 0 homozygotes in GnomAd4. There are 89 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX4	NM_032444.4 link	c.2359G>A	p.Glu787Lys	missense_variant	Exon 12 of 15	ENST00000294008.4	NP_115820.2	Q8IY92-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLX4	ENST00000294008.4 link	c.2359G>A	p.Glu787Lys	missense_variant	Exon 12 of 15	5	NM_032444.4	ENSP00000294008.3		Q8IY92-1

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

185

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00160

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00126

AC:

315

AN:

249766

AF XY:

0.00141

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.00615

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000949

Gnomad NFE exome

AF:

0.00150

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00116

AC:

1694

AN:

1459998

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

848

AN XY:

726424

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.000715

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.00486

AC:

127

AN:

26136

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.000290

AC:

AN:

86252

Gnomad4 FIN exome

AF:

0.000737

AC:

AN:

51554

Gnomad4 NFE exome

AF:

0.00121

AC:

1340

AN:

1111998

Gnomad4 Remaining exome

AF:

0.00131

AC:

AN:

60386

Heterozygous variant carriers

117

234

352

469

586

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00121

AC:

185

AN:

152304

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000866

AC:

0.000866218

AN:

0.000866218

Gnomad4 AMR

AF:

0.000850

AC:

0.000849673

AN:

0.000849673

Gnomad4 ASJ

AF:

0.00404

AC:

0.00403691

AN:

0.00403691

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000621

AC:

0.000621118

AN:

0.000621118

Gnomad4 FIN

AF:

0.000565

AC:

0.000565291

AN:

0.000565291

Gnomad4 NFE

AF:

0.00160

AC:

0.00160223

AN:

0.00160223

Gnomad4 OTH

AF:

0.00189

AC:

0.00189036

AN:

0.00189036

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00166

Hom.:

Bravo

AF:

0.00141

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00122

AC:

148

EpiCase

AF:

0.00218

EpiControl

AF:

0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fanconi anemia complementation group P

Uncertain:2Benign:1

Oct 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 23, 2020

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Uncertain:2Benign:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLX4: BP4 -

Sep 26, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate cell growth similar to wild-type following exposure to Mitomycin C (PMID: 22911665); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast or ovarian cancer, but also in unaffected controls (PMID: 23211700, 22911665, 32546565); Observed in the homozygous state in a cohort of men with infertility (PMID: 36041235); This variant is associated with the following publications: (PMID: 23211700, 22911665, 23840564, 28678401, 32546565, 34426522, 36041235) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Aug 31, 2012

Leiden Open Variation Database

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker. -

Nov 29, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fanconi anemia

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 13, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

SLX4-related disorder

Benign:1

Jan 27, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.71

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.3

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.24

Sift

Benign

0.054

Sift4G

Uncertain

0.021

Polyphen

0.95

Vest4

0.40

MVP

0.71

MPC

0.16

ClinPred

0.034

GERP RS

1.3

Varity_R

0.21

gMVP

0.44

Mutation Taster

=84/16

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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