X-143629117-C-T

Variant names:

• chrX-143629117-C-T
• rs782765655
• NM_001184749.3:c.1992G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001184749.3(SLITRK4):​c.1992G>A​(p.Met664Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,210,315 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 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. M664L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000064 (0 hom. 1 hem.)
• Consequence: SLITRK4 NM_001184749.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12384498).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001184749.3. 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
	SLITRK4	NM_001184749.3	MANE Select	c.1992G>A	p.Met664Ile	missense	Exon 2 of 2	NP_001171678.1	Q8IW52
	SLITRK4	NM_001184750.2		c.1992G>A	p.Met664Ile	missense	Exon 2 of 2	NP_001171679.1	Q8IW52
	SLITRK4	NM_173078.5		c.1992G>A	p.Met664Ile	missense	Exon 2 of 2	NP_775101.1	Q8IW52

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLITRK4	ENST00000356928.2	TSL:2 MANE Select	c.1992G>A	p.Met664Ile	missense	Exon 2 of 2	ENSP00000349400.1	Q8IW52
	SLITRK4	ENST00000338017.8	TSL:1	c.1992G>A	p.Met664Ile	missense	Exon 2 of 2	ENSP00000336627.4	Q8IW52
	SLITRK4	ENST00000596188.2	TSL:1	c.1992G>A	p.Met664Ile	missense	Exon 2 of 2	ENSP00000469205.1	Q8IW52

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112119 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

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: 0.0000375

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183055 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000637 AC: 7 AN: 1098196 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363552

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40499

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000831 AC: 7 AN: 842130

Other (OTH) AF: 0.00 AC: 0 AN: 46096

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112119 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34291

African (AFR) AF: 0.00 AC: 0 AN: 30775

American (AMR) AF: 0.00 AC: 0 AN: 10604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3564

South Asian (SAS) AF: 0.00 AC: 0 AN: 2680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6125

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000375 AC: 2 AN: 53289

Other (OTH) AF: 0.00 AC: 0 AN: 1502

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

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	0.19
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Uncertain	0.97
DEOGEN2	Benign	0.018	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		4.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.35	N
REVEL	Benign	0.074
Sift	Benign	0.42	T
Sift4G	Benign	0.74	T
Polyphen		0.46	P
Vest4		0.20
MutPred		0.32		Gain of sheet (P = 0.0101)
MVP		0.24
ClinPred		0.19	T
GERP RS		3.6
Varity_R		0.42
gMVP		0.70
Mutation Taster		=61/39	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: rs782765655; hg19: chrX-142716933; COSMIC: COSV100567304;