X-143628933-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001184749.3(SLITRK4):​c.2176G>A​(p.Asp726Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,097,548 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign 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. D726E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)
Exomes 𝑓: 0.0000036 ( 0 hom. 3 hem. )

Consequence

SLITRK4
NM_001184749.3 missense

Scores

2
3
12

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.57
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.26134062).
BS2
High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLITRK4NM_001184749.3 linkc.2176G>A p.Asp726Asn missense_variant Exon 2 of 2 ENST00000356928.2 NP_001171678.1 Q8IW52

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLITRK4ENST00000356928.2 linkc.2176G>A p.Asp726Asn missense_variant Exon 2 of 2 2 NM_001184749.3 ENSP00000349400.1 Q8IW52
SLITRK4ENST00000338017.8 linkc.2176G>A p.Asp726Asn missense_variant Exon 2 of 2 1 ENSP00000336627.4 Q8IW52
SLITRK4ENST00000596188.2 linkc.2176G>A p.Asp726Asn missense_variant Exon 2 of 2 1 ENSP00000469205.1 Q8IW52

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
AF:
0.00000364
AC:
4
AN:
1097548
Hom.:
0
Cov.:
30
AF XY:
0.00000827
AC XY:
3
AN XY:
362928
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000331
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000356
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.099
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.74
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.048
T;T;T
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
D;.;.
M_CAP
Pathogenic
0.30
D
MetaRNN
Benign
0.26
T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.69
N;N;N
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-1.4
.;N;N
REVEL
Benign
0.10
Sift
Benign
0.047
.;D;D
Sift4G
Uncertain
0.035
D;D;D
Polyphen
0.0030
B;B;B
Vest4
0.33
MutPred
0.45
Loss of ubiquitination at K729 (P = 0.0346);Loss of ubiquitination at K729 (P = 0.0346);Loss of ubiquitination at K729 (P = 0.0346);
MVP
0.45
ClinPred
0.79
D
GERP RS
5.5
Varity_R
0.17
gMVP
0.41

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-142716749; COSMIC: COSV62023555; API