X-143628931-G-T

Variant names:

• chrX-143628931-G-T
• rs199684349
• NM_001184749.3:c.2178C>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001184749.3(SLITRK4):​c.2178C>A​(p.Asp726Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0003 in 1,209,696 control chromosomes in the GnomAD database, including 1 homozygotes. There are 164 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., 12 hem., cov: 23)
  • Exomes 𝑓: 0.00030 (1 hom. 152 hem.)
• Consequence: SLITRK4 NM_001184749.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009961039).
• BS2: High Hemizygotes in GnomAd4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLITRK4	NM_001184749.3	c.2178C>A	p.Asp726Glu	missense_variant	Exon 2 of 2	ENST00000356928.2	NP_001171678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLITRK4	ENST00000356928.2	c.2178C>A	p.Asp726Glu	missense_variant	Exon 2 of 2	2	NM_001184749.3	ENSP00000349400.1
SLITRK4	ENST00000338017.8	c.2178C>A	p.Asp726Glu	missense_variant	Exon 2 of 2	1		ENSP00000336627.4
SLITRK4	ENST00000596188.2	c.2178C>A	p.Asp726Glu	missense_variant	Exon 2 of 2	1		ENSP00000469205.1

Frequencies

GnomAD3 genomes AF: 0.000312 AC: 35 AN: 112020 Hom.: 0 Cov.: 23 AF XY: 0.000351 AC XY: 12 AN XY: 34204

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

Gnomad ASJ AF: 0.00189

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00185

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000432

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000478 AC: 87 AN: 181867 Hom.: 0 AF XY: 0.000585 AC XY: 39 AN XY: 66641

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00148

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00175

Gnomad FIN exome AF: 0.000189

Gnomad NFE exome AF: 0.000457

Gnomad OTH exome AF: 0.000445

GnomAD4 exome AF: 0.000299 AC: 328 AN: 1097621 Hom.: 1 Cov.: 30 AF XY: 0.000419 AC XY: 152 AN XY: 363005

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00181

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00172

Gnomad4 FIN exome AF: 0.0000742

Gnomad4 NFE exome AF: 0.000189

Gnomad4 OTH exome AF: 0.000456

GnomAD4 genome AF: 0.000312 AC: 35 AN: 112075 Hom.: 0 Cov.: 23 AF XY: 0.000350 AC XY: 12 AN XY: 34269

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000188

Gnomad4 ASJ AF: 0.00189

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000432

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000602 Hom.: 30

Bravo AF: 0.000242

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000535 AC: 65

EpiCase AF: 0.000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2178C>A (p.D726E) alteration is located in exon 2 (coding exon 1) of the SLITRK4 gene. This alteration results from a C to A substitution at nucleotide position 2178, causing the aspartic acid (D) at amino acid position 726 to be replaced by a glutamic acid (E). 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	0.072
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	14
DANN	Benign	0.74
DEOGEN2	Benign	0.016	T;T;T
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.74	T;.;.
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.11	N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.41	.;N;N
REVEL	Benign	0.060
Sift	Benign	1.0	.;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.068
MutPred		0.41		Gain of ubiquitination at K729 (P = 0.0898);Gain of ubiquitination at K729 (P = 0.0898);Gain of ubiquitination at K729 (P = 0.0898);
MVP		0.16
ClinPred		0.0034	T
GERP RS		2.4
Varity_R		0.075
gMVP		0.26

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

Other links and lift over

dbSNP: rs199684349; hg19: chrX-142716747; COSMIC: COSV62024100;