Genetic Variant STX12:p.Leu81Val (chr1-27793585-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_177424.3(STX12):c.241C>G(p.Leu81Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000564 in 1,613,946 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

STX12
NM_177424.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.67

Variant links:

Genes affected

STX12 (HGNC:11430): (syntaxin 12) Predicted to enable SNAP receptor activity and SNARE binding activity. Involved in autophagosome assembly; cholesterol efflux; and protein stabilization. Located in several cellular components, including membrane raft; phagocytic vesicle; and phagophore assembly site. Part of SNARE complex. Colocalizes with BLOC-1 complex. [provided by Alliance of Genome Resources, Apr 2022]

STX12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STX12	NM_177424.3 link	c.241C>G	p.Leu81Val	missense_variant	Exon 3 of 9	ENST00000373943.9	NP_803173.1	Q86Y82

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
STX12	ENST00000373943.9 link	c.241C>G	p.Leu81Val	missense_variant	Exon 3 of 9	1	NM_177424.3	ENSP00000363054.4	Q86Y82
STX12	ENST00000440806.2 link	c.241C>G	p.Leu81Val	missense_variant	Exon 3 of 7	3		ENSP00000392577.2	B1AJQ6
STX12	ENST00000468761.1 link	n.294C>G		non_coding_transcript_exon_variant	Exon 3 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251386

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135866

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727202

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:

0.0000800

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.241C>G (p.L81V) alteration is located in exon 3 (coding exon 3) of the STX12 gene. This alteration results from a C to G substitution at nucleotide position 241, causing the leucine (L) at amino acid position 81 to be replaced by a valine (V). 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

0.41

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.055

T;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.44

T;T

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.4

M;.

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.22

Sift

Benign

0.035

D;T

Sift4G

Uncertain

0.042

D;D

Polyphen

0.35

B;.

Vest4

0.80

MVP

0.55

MPC

0.88

ClinPred

0.74

GERP RS

5.5

Varity_R

0.32

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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