X-145822480-A-G

Variant names:

• chrX-145822480-A-G
• rs1371526689
• NM_032539.5:c.55A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_032539.5(SLITRK2):​c.55A>G​(p.Thr19Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,209,133 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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 0.000018 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000011 (0 hom. 2 hem.)
• Consequence: SLITRK2 NM_032539.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.15

Genes affected

SLITRK2 (HGNC:13449): (SLIT and NTRK like family member 2) This gene encodes an integral membrane protein that contains two N-terminal leucine-rich repeats domains and contains C-terminal regions similar to neurotrophin receptors. The encoded protein may play a role in modulating neurite activity. Alternatively spliced transcript variants encoding the same protein have been described.[provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09854415).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLITRK2	NM_032539.5	c.55A>G	p.Thr19Ala	missense_variant	Exon 5 of 5	ENST00000335565.6	NP_115928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLITRK2	ENST00000335565.6	c.55A>G	p.Thr19Ala	missense_variant	Exon 5 of 5	2	NM_032539.5	ENSP00000334374.5
SLITRK2	ENST00000370490.1	c.55A>G	p.Thr19Ala	missense_variant	Exon 1 of 1	6		ENSP00000359521.1

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111374 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33558

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000190

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000547 AC: 10 AN: 182962 Hom.: 0 AF XY: 0.0000297 AC XY: 2 AN XY: 67416

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000292

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: 0.0000122

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.0000109 AC: 12 AN: 1097759 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 2 AN XY: 363117

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 111374 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33558

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 12, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLITRK2 c.55A>G (p.Thr19Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-05 in 182962 control chromosomes (gnomAD). To our knowledge, no occurrence of c.55A>G in individuals affected with Intellectual Developmental Disorder, X-Linked 111 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.012	T;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.71	.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.099	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.38	N;N
REVEL	Benign	0.21
Sift	Benign	0.49	T;T
Sift4G	Benign	0.93	T;T
Polyphen		0.0010	B;B
Vest4		0.20
MutPred		0.29		Gain of ubiquitination at K23 (P = 0.1103);Gain of ubiquitination at K23 (P = 0.1103);
MVP		0.83
MPC		0.53
ClinPred		0.086	T
GERP RS		4.6
Varity_R		0.095
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1371526689; hg19: chrX-144903998;