Genetic Variant SLITRK4:p.Met664Thr (chrX-143629118-A-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001184749.3(SLITRK4):c.1991T>C(p.Met664Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,210,385 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000021 ( 0 hom. 9 hem. )

Consequence

SLITRK4
NM_001184749.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57

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 -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLITRK4	NM_001184749.3 link	c.1991T>C	p.Met664Thr	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.1991T>C	p.Met664Thr	missense_variant	Exon 2 of 2	2	NM_001184749.3	ENSP00000349400.1	Q8IW52
SLITRK4	ENST00000338017.8 link	c.1991T>C	p.Met664Thr	missense_variant	Exon 2 of 2	1		ENSP00000336627.4	Q8IW52
SLITRK4	ENST00000596188.2 link	c.1991T>C	p.Met664Thr	missense_variant	Exon 2 of 2	1		ENSP00000469205.1	Q8IW52

Frequencies

GnomAD3 genomes

AF:

0.00000892

AC:

AN:

112167

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34341

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000328

AC:

AN:

183087

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

67591

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:

0.0000735

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000209

AC:

AN:

1098218

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

363572

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000273

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000892

AC:

AN:

112167

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34341

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

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

Dec 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1991T>C (p.M664T) alteration is located in exon 2 (coding exon 1) of the SLITRK4 gene. This alteration results from a T to C substitution at nucleotide position 1991, causing the methionine (M) at amino acid position 664 to be replaced by a threonine (T). 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

0.18

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.064

T;T;T

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.84

T;.;.

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.48

T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.97

L;L;L

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.1

.;N;N

REVEL

Benign

0.23

Sift

Uncertain

0.013

.;D;D

Sift4G

Benign

0.23

T;T;T

Polyphen

0.96

D;D;D

Vest4

0.54

MVP

0.24

ClinPred

0.35

GERP RS

5.4

Varity_R

0.76

gMVP

0.80

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