Genetic Variant SLX4:p.Ile1421Val (chr16-3589377-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_032444.4(SLX4):c.4261A>G(p.Ile1421Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000417 in 1,438,838 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1421F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

SLX4
NM_032444.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.41

Publications

9 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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022637904).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLX4	NM_032444.4 link	c.4261A>G	p.Ile1421Val	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.4261A>G	p.Ile1421Val	missense_variant	Exon 12 of 15	5	NM_032444.4	ENSP00000294008.3		Q8IY92-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000126

AC:

AN:

239028

AF XY:

0.0000154

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:

0.0000491

Gnomad NFE exome

AF:

0.0000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000417

AC:

AN:

1438838

Hom.:

Cov.:

AF XY:

0.00000562

AC XY:

AN XY:

712296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32874

American (AMR)

AF:

0.00

AC:

AN:

43210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25048

East Asian (EAS)

AF:

0.00

AC:

AN:

39244

South Asian (SAS)

AF:

0.00

AC:

AN:

84820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51202

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.00000364

AC:

AN:

1097516

Other (OTH)

AF:

0.0000169

AC:

AN:

59254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Fanconi anemia complementation group P

Uncertain:1

Mar 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.011

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.073

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.47

M_CAP

Benign

0.017

MetaRNN

Benign

0.023

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.44

PhyloP100

-2.4

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.26

REVEL

Benign

0.0060

Sift

Benign

0.50

Sift4G

Benign

0.72

Polyphen

0.0020

Vest4

0.099

MutPred

0.17

Gain of phosphorylation at S1417 (P = 0.2469);

MVP

0.13

MPC

0.049

ClinPred

0.019

GERP RS

-4.0

Varity_R

0.016

gMVP

0.11

Mutation Taster

=93/7

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over