NM_032539.5:c.10G>A

Variant names:

• chrX-145822435-G-A
• rs149353052
• NM_032539.5:c.10G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_032539.5(SLITRK2):​c.10G>A​(p.Gly4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,203,201 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 64 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G4C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., 3 hem., cov: 21)
  • Exomes 𝑓: 0.00018 (0 hom. 61 hem.)
• Consequence: SLITRK2 NM_032539.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.60
• Publications: 2 publications found

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]

SLITRK2 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, X-linked 111

  Inheritance: XL Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.1956 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to intellectual developmental disorder, X-linked 111.
• BP4: Computational evidence support a benign effect (MetaRNN=0.080161095).
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032539.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLITRK2	NM_032539.5	MANE Select	c.10G>A	p.Gly4Ser	missense	Exon 5 of 5	NP_115928.1	Q9H156-1
	SLITRK2	NM_001144003.3		c.10G>A	p.Gly4Ser	missense	Exon 5 of 5	NP_001137475.1	Q9H156-1
	SLITRK2	NM_001144004.3		c.10G>A	p.Gly4Ser	missense	Exon 5 of 5	NP_001137476.1	Q9H156-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLITRK2	ENST00000335565.6	TSL:2 MANE Select	c.10G>A	p.Gly4Ser	missense	Exon 5 of 5	ENSP00000334374.5	Q9H156-1
	SLITRK2	ENST00000370490.1	TSL:6	c.10G>A	p.Gly4Ser	missense	Exon 1 of 1	ENSP00000359521.1	Q9H156-1
	SLITRK2	ENST00000867861.1		c.10G>A	p.Gly4Ser	missense	Exon 5 of 5	ENSP00000537920.1

Frequencies

GnomAD3 genomes AF: 0.0000539 AC: 6 AN: 111351 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.000131

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: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000692 AC: 12 AN: 173324 AF XY: 0.0000340

Gnomad AFR exome AF: 0.0000765

Gnomad AMR exome AF: 0.0000378

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000128

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000180 AC: 196 AN: 1091850 Hom.: 0 Cov.: 29 AF XY: 0.000170 AC XY: 61 AN XY: 358422

African (AFR) AF: 0.0000762 AC: 2 AN: 26247

American (AMR) AF: 0.0000289 AC: 1 AN: 34641

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18829

East Asian (EAS) AF: 0.00 AC: 0 AN: 30171

South Asian (SAS) AF: 0.00 AC: 0 AN: 52622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40337

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4007

European-Non Finnish (NFE) AF: 0.000228 AC: 191 AN: 839191

Other (OTH) AF: 0.0000437 AC: 2 AN: 45805

GnomAD4 genome AF: 0.0000539 AC: 6 AN: 111351 Hom.: 0 Cov.: 21 AF XY: 0.0000895 AC XY: 3 AN XY: 33525

African (AFR) AF: 0.000131 AC: 4 AN: 30486

American (AMR) AF: 0.00 AC: 0 AN: 10525

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3548

South Asian (SAS) AF: 0.00 AC: 0 AN: 2618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5983

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53139

Other (OTH) AF: 0.00 AC: 0 AN: 1492

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000577 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.6
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.026
Sift	Benign	0.12	T
Sift4G	Benign	0.88	T
Polyphen		0.012	B
Vest4		0.13
MVP		0.84
MPC		0.54
ClinPred		0.031	T
GERP RS		2.8
Varity_R		0.076
gMVP		0.33
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs149353052; hg19: chrX-144903953; COSMIC: COSV100157818; COSMIC: COSV100157818;