rs199684349

Variant names:

• chrX-143628931-G-T
• rs199684349
• NM_001184749.3:c.2178C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-143628931-G-T
• chrX-143628931-G-C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001184749.3(SLITRK4):​c.2178C>A​(p.Asp726Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0003 in 1,209,696 control chromosomes in the GnomAD database, including 1 homozygotes. There are 164 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 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. D726Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., 12 hem., cov: 23)
  • Exomes 𝑓: 0.00030 (1 hom. 152 hem.)
• Consequence: SLITRK4 NM_001184749.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009961039).
• BS2: High Hemizygotes in GnomAd4 at 12 gene

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.2178C>A	p.Asp726Glu	missense	Exon 2 of 2	NP_001171678.1	Q8IW52
	SLITRK4	NM_001184750.2		c.2178C>A	p.Asp726Glu	missense	Exon 2 of 2	NP_001171679.1	Q8IW52
	SLITRK4	NM_173078.5		c.2178C>A	p.Asp726Glu	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.2178C>A	p.Asp726Glu	missense	Exon 2 of 2	ENSP00000349400.1	Q8IW52
	SLITRK4	ENST00000338017.8	TSL:1	c.2178C>A	p.Asp726Glu	missense	Exon 2 of 2	ENSP00000336627.4	Q8IW52
	SLITRK4	ENST00000596188.2	TSL:1	c.2178C>A	p.Asp726Glu	missense	Exon 2 of 2	ENSP00000469205.1	Q8IW52

Frequencies

GnomAD3 genomes AF: 0.000312 AC: 35 AN: 112020 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

Gnomad ASJ AF: 0.00189

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00185

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000432

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000478 AC: 87 AN: 181867 AF XY: 0.000585

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00148

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000189

Gnomad NFE exome AF: 0.000457

Gnomad OTH exome AF: 0.000445

GnomAD4 exome AF: 0.000299 AC: 328 AN: 1097621 Hom.: 1 Cov.: 30 AF XY: 0.000419 AC XY: 152 AN XY: 363005

African (AFR) AF: 0.0000379 AC: 1 AN: 26386

American (AMR) AF: 0.000114 AC: 4 AN: 35181

Ashkenazi Jewish (ASJ) AF: 0.00181 AC: 35 AN: 19368

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00172 AC: 93 AN: 54063

European-Finnish (FIN) AF: 0.0000742 AC: 3 AN: 40410

Middle Eastern (MID) AF: 0.00290 AC: 12 AN: 4136

European-Non Finnish (NFE) AF: 0.000189 AC: 159 AN: 841798

Other (OTH) AF: 0.000456 AC: 21 AN: 46075

GnomAD4 genome AF: 0.000312 AC: 35 AN: 112075 Hom.: 0 Cov.: 23 AF XY: 0.000350 AC XY: 12 AN XY: 34269

African (AFR) AF: 0.00 AC: 0 AN: 30857

American (AMR) AF: 0.000188 AC: 2 AN: 10619

Ashkenazi Jewish (ASJ) AF: 0.00189 AC: 5 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3537

South Asian (SAS) AF: 0.00186 AC: 5 AN: 2695

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000432 AC: 23 AN: 53200

Other (OTH) AF: 0.00 AC: 0 AN: 1536

Alfa AF: 0.000566 Hom.: 30

Bravo AF: 0.000242

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000535 AC: 65

EpiCase AF: 0.000545

EpiControl AF: 0.000119

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	0.072
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	14
DANN	Benign	0.74
DEOGEN2	Benign	0.016	T
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.11	N
PhyloP100		1.5
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.060
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.068
MutPred		0.41		Gain of ubiquitination at K729 (P = 0.0898)
MVP		0.16
ClinPred		0.0034	T
GERP RS		2.4
Varity_R		0.075
gMVP		0.26
Mutation Taster		=100/0	polymorphism (auto)

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: rs199684349; hg19: chrX-142716747; COSMIC: COSV62024100;