Genetic Variant SLITRK4:p.Leu339Val (chrX-143630094-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001184749.3(SLITRK4):c.1015C>G(p.Leu339Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000487 in 1,210,455 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000048 ( 0 hom. 17 hem. )

Consequence

SLITRK4
NM_001184749.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.62

Variant links:

Genes affected

SLITRK4 (HGNC:23502): (SLIT and NTRK like family member 4) This gene encodes a transmembrane protein belonging to the the SLITRK family. These family members include two N-terminal leucine-rich repeat domains similar to those found in the axonal growth-controlling protein SLIT, as well as C-terminal regions similar to neurotrophin receptors. Studies of an homologous protein in mouse suggest that this family member functions to suppress neurite outgrowth. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

SLITRK4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12766767).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLITRK4	NM_001184749.3 link	c.1015C>G	p.Leu339Val	missense_variant	Exon 2 of 2	ENST00000356928.2	NP_001171678.1	Q8IW52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLITRK4	ENST00000356928.2 link	c.1015C>G	p.Leu339Val	missense_variant	Exon 2 of 2	2	NM_001184749.3	ENSP00000349400.1	Q8IW52
SLITRK4	ENST00000338017.8 link	c.1015C>G	p.Leu339Val	missense_variant	Exon 2 of 2	1		ENSP00000336627.4	Q8IW52
SLITRK4	ENST00000596188.2 link	c.1015C>G	p.Leu339Val	missense_variant	Exon 2 of 2	1		ENSP00000469205.1	Q8IW52

Frequencies

GnomAD3 genomes

AF:

0.0000534

AC:

AN:

112309

Hom.:

Cov.:

AF XY:

0.0000581

AC XY:

AN XY:

34437

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000938

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183415

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67861

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000489

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000483

AC:

AN:

1098146

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

363502

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000606

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000534

AC:

AN:

112309

Hom.:

Cov.:

AF XY:

0.0000581

AC XY:

AN XY:

34437

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000938

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1015C>G (p.L339V) alteration is located in exon 2 (coding exon 1) of the SLITRK4 gene. This alteration results from a C to G substitution at nucleotide position 1015, causing the leucine (L) at amino acid position 339 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.027

T;T;T

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.80

T;.;.

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;L;L

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.040

.;N;N

REVEL

Benign

0.038

Sift

Benign

0.18

.;T;T

Sift4G

Benign

0.51

T;T;T

Polyphen

0.0050

B;B;B

Vest4

0.098

MVP

0.35

ClinPred

0.13

GERP RS

5.6

Varity_R

0.12

gMVP

0.49

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