Genetic Variant SLITRK4:p.Pro596Leu (chrX-143629322-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001184749.3(SLITRK4):c.1787C>T(p.Pro596Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,210,218 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 57 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 0.00012 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.00016 ( 0 hom. 55 hem. )

Consequence

SLITRK4
NM_001184749.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32799286).

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.1787C>T	p.Pro596Leu	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.1787C>T	p.Pro596Leu	missense_variant	Exon 2 of 2	2	NM_001184749.3	ENSP00000349400.1	Q8IW52
SLITRK4	ENST00000338017.8 link	c.1787C>T	p.Pro596Leu	missense_variant	Exon 2 of 2	1		ENSP00000336627.4	Q8IW52
SLITRK4	ENST00000596188.2 link	c.1787C>T	p.Pro596Leu	missense_variant	Exon 2 of 2	1		ENSP00000469205.1	Q8IW52

Frequencies

GnomAD3 genomes

AF:

0.000116

AC:

AN:

112209

Hom.:

Cov.:

AF XY:

0.0000582

AC XY:

AN XY:

34365

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000244

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000930

AC:

AN:

182848

Hom.:

AF XY:

0.0000889

AC XY:

AN XY:

67454

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:

0.0000626

Gnomad NFE exome

AF:

0.000196

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000161

AC:

177

AN:

1097955

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

AN XY:

363319

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

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:

0.0000493

Gnomad4 NFE exome

AF:

0.000202

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.000116

AC:

AN:

112263

Hom.:

Cov.:

AF XY:

0.0000581

AC XY:

AN XY:

34429

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000244

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1787C>T (p.P596L) alteration is located in exon 2 (coding exon 1) of the SLITRK4 gene. This alteration results from a C to T substitution at nucleotide position 1787, causing the proline (P) at amino acid position 596 to be replaced by a leucine (L). 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

0.095

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.067

T;T;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;.;.

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.33

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.7

L;L;L

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.4

.;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.025

.;D;D

Sift4G

Benign

0.16

T;T;T

Polyphen

0.11

B;B;B

Vest4

0.54

MVP

0.37

ClinPred

0.18

GERP RS

5.7

Varity_R

0.31

gMVP

0.75

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