Genetic Variant SLX4:p.Leu3Val (chr16-3608958-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032444.4(SLX4):c.7C>G(p.Leu3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L3R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.102

Publications

1 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SLX4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.061974376).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX4	NM_032444.4 link	c.7C>G	p.Leu3Val	missense_variant	Exon 2 of 15	ENST00000294008.4	NP_115820.2	Q8IY92-1
SLX4	XM_024450471.2 link	c.7C>G	p.Leu3Val	missense_variant	Exon 2 of 15		XP_024306239.1
SLX4	XM_011522715.4 link	c.7C>G	p.Leu3Val	missense_variant	Exon 2 of 15		XP_011521017.1
SLX4	XR_007064923.1 link	n.656C>G		non_coding_transcript_exon_variant	Exon 2 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLX4	ENST00000294008.4 link	c.7C>G	p.Leu3Val	missense_variant	Exon 2 of 15	5	NM_032444.4	ENSP00000294008.3	Q8IY92-1
SLX4	ENST00000466154.5 link	n.302C>G		non_coding_transcript_exon_variant	Exon 1 of 7	1
SLX4	ENST00000486524.1 link	n.635C>G		non_coding_transcript_exon_variant	Exon 2 of 4	2
SLX4	ENST00000697859.1 link	n.629C>G		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250154

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460666

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726670

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5660

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111970

Other (OTH)

AF:

0.0000166

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.45

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.019

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.21

M_CAP

Benign

0.014

MetaRNN

Benign

0.062

MetaSVM

Benign

-0.85

MutationAssessor

Benign

-0.69

PhyloP100

0.10

PrimateAI

Benign

0.25

PROVEAN

Benign

0.33

REVEL

Benign

0.071

Sift

Pathogenic

0.0

Sift4G

Benign

1.0

Polyphen

0.81

Vest4

0.13

MutPred

0.15

Gain of sheet (P = 0.0344);

MVP

0.16

MPC

0.056

ClinPred

0.089

GERP RS

0.65

Varity_R

0.061

gMVP

0.0098

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over