Variant 3-94014825-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001001850.3(STX19):c.445T>C(p.Phe149Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

STX19
NM_001001850.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.12

Variant links:

Genes affected

STX19 (HGNC:19300): (syntaxin 19) Predicted to enable SNAP receptor activity and SNARE binding activity. Predicted to be involved in intracellular protein transport; synaptic vesicle fusion to presynaptic active zone membrane; and vesicle docking. Predicted to be part of SNARE complex. Predicted to be active in presynaptic active zone membrane and synaptic vesicle. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

STX19 links:

ARL13B (HGNC:25419): (ADP ribosylation factor like GTPase 13B) This gene encodes a member of the ADP-ribosylation factor-like family. The encoded protein is a small GTPase that contains both N-terminal and C-terminal guanine nucleotide-binding motifs. This protein is localized in the cilia and plays a role in cilia formation and in maintenance of cilia. Mutations in this gene are the cause of Joubert syndrome 8. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

ARL13B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06615186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STX19	NM_001001850.3 linkuse as main transcript	c.445T>C	p.Phe149Leu	missense_variant	2/2	ENST00000315099.3
ARL13B	NM_001174150.2 linkuse as main transcript	c.380+10917A>G		intron_variant		ENST00000394222.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STX19	ENST00000315099.3 linkuse as main transcript	c.445T>C	p.Phe149Leu	missense_variant	2/2	1	NM_001001850.3	P1
ARL13B	ENST00000394222.8 linkuse as main transcript	c.380+10917A>G		intron_variant		1	NM_001174150.2	P1	Q3SXY8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250824

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135536

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461776

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.445T>C (p.F149L) alteration is located in exon 2 (coding exon 1) of the STX19 gene. This alteration results from a T to C substitution at nucleotide position 445, causing the phenylalanine (F) at amino acid position 149 to be replaced by a leucine (L). 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

Uncertain

0.35

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.013

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.54

M_CAP

Benign

0.0019

MetaRNN

Benign

0.066

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

D;D;D;D;D;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.23

REVEL

Benign

0.015

Sift

Benign

0.66

Sift4G

Benign

0.81

Polyphen

0.0

Vest4

0.075

MutPred

0.40

Gain of MoRF binding (P = 0.1493);

MVP

0.51

MPC

0.0089

ClinPred

0.038

GERP RS

2.3

Varity_R

0.061

gMVP

0.25

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over