3-165188171-C-T

Variant names:

• chr3-165188171-C-T
• rs148918085
• NM_001318810.2:c.2660G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001318810.2(SLITRK3):​c.2660G>A​(p.Arg887Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000711 in 1,613,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00072 (0 hom.)
• Consequence: SLITRK3 NM_001318810.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.33

Genes affected

SLITRK3 (HGNC:23501): (SLIT and NTRK like family member 3) This gene encodes a member of the Slitrk family of structurally related transmembrane proteins that are involved in controlling neurite outgrowth. The encoded protein contains two leucine-rich repeat (LRR) domains and a C-terminal domain that is partially similar to Trk neurotrophin receptor protein. Enhanced expression of this gene was found in tissue from several different types of tumors. Alternative splicing results in multiple transcript variants, all encoding the same protein. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.034258425).
• BS2: High AC in GnomAd4 at 92 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLITRK3	NM_001318810.2	c.2660G>A	p.Arg887Gln	missense_variant	Exon 2 of 2	ENST00000475390.2	NP_001305739.1
SLITRK3	NM_001318811.2	c.2660G>A	p.Arg887Gln	missense_variant	Exon 2 of 2		NP_001305740.1
SLITRK3	NM_014926.4	c.2660G>A	p.Arg887Gln	missense_variant	Exon 2 of 2		NP_055741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLITRK3	ENST00000475390.2	c.2660G>A	p.Arg887Gln	missense_variant	Exon 2 of 2	1	NM_001318810.2	ENSP00000420091.1
SLITRK3	ENST00000241274.3	c.2660G>A	p.Arg887Gln	missense_variant	Exon 2 of 2	1		ENSP00000241274.3

Frequencies

GnomAD3 genomes AF: 0.000606 AC: 92 AN: 151780 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00329

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000450 AC: 113 AN: 251262 Hom.: 0 AF XY: 0.000479 AC XY: 65 AN XY: 135792

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000695

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000722 AC: 1056 AN: 1461842 Hom.: 0 Cov.: 34 AF XY: 0.000714 AC XY: 519 AN XY: 727230

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000892

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000606 AC: 92 AN: 151780 Hom.: 0 Cov.: 31 AF XY: 0.000675 AC XY: 50 AN XY: 74112

Gnomad4 AFR AF: 0.0000726

Gnomad4 AMR AF: 0.00329

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000508 Hom.: 0

Bravo AF: 0.000661

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2660G>A (p.R887Q) alteration is located in exon 2 (coding exon 1) of the SLITRK3 gene. This alteration results from a G to A substitution at nucleotide position 2660, causing the arginine (R) at amino acid position 887 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.80	.;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.034	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.46	N;N
REVEL	Benign	0.098
Sift	Benign	0.079	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.89	P;P
Vest4		0.28
MVP		0.50
MPC		0.30
ClinPred		0.019	T
GERP RS		5.8
Varity_R		0.13
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs148918085; hg19: chr3-164905959;