X-143629826-C-A

Variant names:

• chrX-143629826-C-A
• rs782819249
• NM_001184749.3:c.1283G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001184749.3(SLITRK4):​c.1283G>T​(p.Arg428Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,096,467 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. R428H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: SLITRK4 NM_001184749.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.04
• Publications: 0 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

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.1283G>T	p.Arg428Leu	missense	Exon 2 of 2	NP_001171678.1	Q8IW52
	SLITRK4	NM_001184750.2		c.1283G>T	p.Arg428Leu	missense	Exon 2 of 2	NP_001171679.1	Q8IW52
	SLITRK4	NM_173078.5		c.1283G>T	p.Arg428Leu	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.1283G>T	p.Arg428Leu	missense	Exon 2 of 2	ENSP00000349400.1	Q8IW52
	SLITRK4	ENST00000338017.8	TSL:1	c.1283G>T	p.Arg428Leu	missense	Exon 2 of 2	ENSP00000336627.4	Q8IW52
	SLITRK4	ENST00000596188.2	TSL:1	c.1283G>T	p.Arg428Leu	missense	Exon 2 of 2	ENSP00000469205.1	Q8IW52

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096467 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 361981

African (AFR) AF: 0.00 AC: 0 AN: 26372

American (AMR) AF: 0.00 AC: 0 AN: 35155

Ashkenazi Jewish (ASJ) AF: 0.0000517 AC: 1 AN: 19347

East Asian (EAS) AF: 0.00 AC: 0 AN: 30175

South Asian (SAS) AF: 0.00 AC: 0 AN: 54045

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40519

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840695

Other (OTH) AF: 0.00 AC: 0 AN: 46030

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.57		Loss of MoRF binding (P = 0.1464)
MVP		0.28
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.68
gMVP		0.59
Mutation Taster		=55/45	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: rs782819249; hg19: chrX-142717642;