Genetic Variant SLITRK4:p.Arg780His (chrX-143628770-C-T) – 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.2339G>A(p.Arg780His) variant causes a missense change. The variant allele was found at a frequency of 0.0000246 in 1,097,319 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.000025 ( 0 hom. 14 hem. )

Consequence

SLITRK4
NM_001184749.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.74

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10240549).

BS2

High Hemizygotes in GnomAdExome4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLITRK4	NM_001184749.3 link	c.2339G>A	p.Arg780His	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.2339G>A	p.Arg780His	missense_variant	Exon 2 of 2	2	NM_001184749.3	ENSP00000349400.1	Q8IW52
SLITRK4	ENST00000338017.8 link	c.2339G>A	p.Arg780His	missense_variant	Exon 2 of 2	1		ENSP00000336627.4	Q8IW52
SLITRK4	ENST00000596188.2 link	c.2339G>A	p.Arg780His	missense_variant	Exon 2 of 2	1		ENSP00000469205.1	Q8IW52

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000550

AC:

AN:

181883

Hom.:

AF XY:

0.0000602

AC XY:

AN XY:

66497

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:

0.000374

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000245

Gnomad OTH exome

AF:

0.000223

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1097319

Hom.:

Cov.:

AF XY:

0.0000386

AC XY:

AN XY:

362763

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.0000249

Gnomad4 NFE exome

AF:

0.0000107

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000727

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2339G>A (p.R780H) alteration is located in exon 2 (coding exon 1) of the SLITRK4 gene. This alteration results from a G to A substitution at nucleotide position 2339, causing the arginine (R) at amino acid position 780 to be replaced by a histidine (H). 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

0.093

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.023

T;T;T

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.91

D;.;.

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;N;N

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.21

.;N;N

REVEL

Benign

0.052

Sift

Benign

0.074

.;T;T

Sift4G

Benign

0.52

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.23

MutPred

0.23

Gain of ubiquitination at K784 (P = 0.0435);Gain of ubiquitination at K784 (P = 0.0435);Gain of ubiquitination at K784 (P = 0.0435);

MVP

0.40

ClinPred

0.072

GERP RS

5.4

Varity_R

0.081

gMVP

0.32

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