X-143629913-T-A

Variant names:

• chrX-143629913-T-A
• rs782537663
• NM_001184749.3:c.1196A>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001184749.3(SLITRK4):​c.1196A>T​(p.Asp399Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000298 in 1,209,974 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000028 (0 hom. 10 hem.)
• Consequence: SLITRK4 NM_001184749.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.79

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30185625).
• BS2: High Hemizygotes in GnomAdExome4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLITRK4	NM_001184749.3	c.1196A>T	p.Asp399Val	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.1196A>T	p.Asp399Val	missense_variant	Exon 2 of 2	2	NM_001184749.3	ENSP00000349400.1
SLITRK4	ENST00000338017.8	c.1196A>T	p.Asp399Val	missense_variant	Exon 2 of 2	1		ENSP00000336627.4
SLITRK4	ENST00000596188.2	c.1196A>T	p.Asp399Val	missense_variant	Exon 2 of 2	1		ENSP00000469205.1

Frequencies

GnomAD3 genomes AF: 0.0000446 AC: 5 AN: 112088 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34258

Gnomad AFR AF: 0.0000324

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: 0.0000751

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000273 AC: 5 AN: 183050 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67520

Gnomad AFR exome AF: 0.0000760

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: 0.0000489

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000282 AC: 31 AN: 1097886 Hom.: 0 Cov.: 33 AF XY: 0.0000275 AC XY: 10 AN XY: 363244

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: 0.0000344

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000446 AC: 5 AN: 112088 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34258

Gnomad4 AFR AF: 0.0000324

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: 0.0000751

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 1

Bravo AF: 0.0000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1196A>T (p.D399V) alteration is located in exon 2 (coding exon 1) of the SLITRK4 gene. This alteration results from a A to T substitution at nucleotide position 1196, causing the aspartic acid (D) at amino acid position 399 to be replaced by a valine (V). 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	0.20
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T;T;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;.;.
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.8	L;L;L
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.3	.;D;D
REVEL	Benign	0.13
Sift	Uncertain	0.0040	.;D;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		0.14	B;B;B
Vest4		0.25
MutPred		0.60		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.22
ClinPred		0.15	T
GERP RS		5.3
Varity_R		0.40
gMVP		0.41

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: rs782537663; hg19: chrX-142717729;