Genetic Variant NM_001184749.3:c.1654G>C (chrX-143629455-C-G) – 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.1654G>C(p.Gly552Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,098,245 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000036 ( 0 hom. 3 hem. )

Consequence

SLITRK4
NM_001184749.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.37598112).

BS2

High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLITRK4	NM_001184749.3 link	c.1654G>C	p.Gly552Arg	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.1654G>C	p.Gly552Arg	missense_variant	Exon 2 of 2	2	NM_001184749.3	ENSP00000349400.1	Q8IW52
SLITRK4	ENST00000338017.8 link	c.1654G>C	p.Gly552Arg	missense_variant	Exon 2 of 2	1		ENSP00000336627.4	Q8IW52
SLITRK4	ENST00000596188.2 link	c.1654G>C	p.Gly552Arg	missense_variant	Exon 2 of 2	1		ENSP00000469205.1	Q8IW52

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183507

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67937

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:

0.000105

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000364

AC:

AN:

1098245

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

363599

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:

0.0000739

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

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

not specified

Uncertain:1

Jun 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1654G>C (p.G552R) alteration is located in exon 2 (coding exon 1) of the SLITRK4 gene. This alteration results from a G to C substitution at nucleotide position 1654, causing the glycine (G) at amino acid position 552 to be replaced by an arginine (R). 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

0.17

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.072

T;T;T

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

D;.;.

M_CAP

Pathogenic

0.60

MetaRNN

Benign

0.38

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.5

L;L;L

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.0

.;N;N

REVEL

Benign

0.19

Sift

Benign

0.090

.;T;T

Sift4G

Benign

0.39

T;T;T

Polyphen

0.29

B;B;B

Vest4

0.44

MutPred

0.39

Gain of MoRF binding (P = 0.0794);Gain of MoRF binding (P = 0.0794);Gain of MoRF binding (P = 0.0794);

MVP

0.71

ClinPred

0.42

GERP RS

5.4

Varity_R

0.21

gMVP

0.81

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