NM_032539.5:c.535C>A

Variant names:

• chrX-145822960-C-A
• rs374163921
• NM_032539.5:c.535C>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_032539.5(SLITRK2):​c.535C>A​(p.Arg179Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,004 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R179C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: SLITRK2 NM_032539.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

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.535C>A	p.Arg179Ser	missense	Exon 5 of 5	NP_115928.1	Q9H156-1
	SLITRK2	NM_001144003.3		c.535C>A	p.Arg179Ser	missense	Exon 5 of 5	NP_001137475.1	Q9H156-1
	SLITRK2	NM_001144004.3		c.535C>A	p.Arg179Ser	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.535C>A	p.Arg179Ser	missense	Exon 5 of 5	ENSP00000334374.5	Q9H156-1
	SLITRK2	ENST00000370490.1	TSL:6	c.535C>A	p.Arg179Ser	missense	Exon 1 of 1	ENSP00000359521.1	Q9H156-1
	SLITRK2	ENST00000867861.1		c.535C>A	p.Arg179Ser	missense	Exon 5 of 5	ENSP00000537920.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098004 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363360

African (AFR) AF: 0.00 AC: 0 AN: 26394

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841933

Other (OTH) AF: 0.00 AC: 0 AN: 46090

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.47	N
PhyloP100		7.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.64		Loss of methylation at R179 (P = 0.0257)
MVP		0.72
MPC		1.5
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.90
gMVP		0.84
Mutation Taster		=39/61	disease causing

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: rs374163921; hg19: chrX-144904478;