rs139287784

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_032444.4(SLX4):c.2975G>A(p.Gly992Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000497 in 1,614,196 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.00054 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00049 ( 1 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3

Conservation

PhyloP100: 0.448

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

Fanconi anemia complementation group P
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
familial ovarian cancer
Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

SLX4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006367922).

BP6

Variant 16-3590663-C-T is Benign according to our data. Variant chr16-3590663-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 319162.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000538 (82/152360) while in subpopulation AMR AF = 0.00183 (28/15310). AF 95% confidence interval is 0.0013. There are 0 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032444.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	NM_032444.4	MANE Select	c.2975G>A	p.Gly992Glu	missense	Exon 12 of 15	NP_115820.2	Q8IY92-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	ENST00000294008.4	TSL:5 MANE Select	c.2975G>A	p.Gly992Glu	missense	Exon 12 of 15	ENSP00000294008.3	Q8IY92-1

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000534

AC:

134

AN:

251152

AF XY:

0.000486

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000423

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000493

AC:

721

AN:

1461836

Hom.:

Cov.:

AF XY:

0.000501

AC XY:

364

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33480

American (AMR)

AF:

0.00157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00199

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000255

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.0175

AC:

101

AN:

5768

European-Non Finnish (NFE)

AF:

0.000342

AC:

380

AN:

1112010

Other (OTH)

AF:

0.00132

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

107

160

214

267

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000538

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.000264

AC:

AN:

41598

American (AMR)

AF:

0.00183

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.000586

Hom.:

Bravo

AF:

0.000608

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000420

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000652

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fanconi anemia complementation group P (3)

not provided (3)

Fanconi anemia (2)

not specified (1)

SLX4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.9

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.20

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.49

M_CAP

Benign

0.062

MetaRNN

Benign

0.0064

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.7

PhyloP100

0.45

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.9

REVEL

Benign

0.096

Sift

Benign

0.088

Sift4G

Benign

0.13

Polyphen

0.81

Vest4

0.25

MVP

0.18

MPC

0.27

ClinPred

0.019

GERP RS

1.1

Varity_R

0.043

gMVP

0.19

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over