6-144186653-T-G

Position:

chr6-144186653-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003764.4(STX11):c.26T>G(p.Leu9Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000764 in 1,614,122 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00077 ( 2 hom. )

Consequence

STX11
NM_003764.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 1.27

Variant links:

Genes affected

STX11 (HGNC:11429): (syntaxin 11) This gene encodes a member of the syntaxin family. Syntaxins have been implicated in the targeting and fusion of intracellular transport vesicles. This family member may regulate protein transport among late endosomes and the trans-Golgi network. Mutations in this gene have been associated with familial hemophagocytic lymphohistiocytosis. [provided by RefSeq, Jul 2008]

STX11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006764263).

BP6

Variant 6-144186653-T-G is Benign according to our data. Variant chr6-144186653-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 355598.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000696 (106/152322) while in subpopulation NFE AF= 0.00129 (88/68020). AF 95% confidence interval is 0.00107. There are 0 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STX11	NM_003764.4 linkuse as main transcript	c.26T>G	p.Leu9Arg	missense_variant	2/2	ENST00000367568.5	NP_003755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
STX11	ENST00000367568.5 linkuse as main transcript	c.26T>G	p.Leu9Arg	missense_variant	2/2	1	NM_003764.4	ENSP00000356540	P1
STX11	ENST00000698355.1 linkuse as main transcript	c.26T>G	p.Leu9Arg	missense_variant	3/3			ENSP00000513678	P1
STX11	ENST00000698356.1 linkuse as main transcript	c.26T>G	p.Leu9Arg	missense_variant	4/4			ENSP00000513679	P1
STX11	ENST00000698357.1 linkuse as main transcript	c.26T>G	p.Leu9Arg	missense_variant	2/2			ENSP00000513680	P1

Frequencies

GnomAD3 genomes

AF:

0.000696

AC:

106

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000852

AC:

214

AN:

251302

Hom.:

AF XY:

0.000817

AC XY:

111

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00199

Gnomad NFE exome

AF:

0.00145

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000771

AC:

1127

AN:

1461800

Hom.:

Cov.:

AF XY:

0.000784

AC XY:

570

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00221

Gnomad4 NFE exome

AF:

0.000868

Gnomad4 OTH exome

AF:

0.000646

GnomAD4 genome

AF:

0.000696

AC:

106

AN:

152322

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.00129

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.00101

Hom.:

Bravo

AF:

0.000480

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00110

AC:

133

EpiCase

AF:

0.000872

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 4

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	STX11: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2019	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

The c.26T>G (p.L9R) alteration is located in exon 2 (coding exon 1) of the STX11 gene. This alteration results from a T to G substitution at nucleotide position 26, causing the leucine (L) at amino acid position 9 to be replaced by an arginine (R). 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

0.068

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.016

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.40

M_CAP

Benign

0.0025

MetaRNN

Benign

0.0068

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

PrimateAI

Benign

0.37

PROVEAN

Benign

1.1

REVEL

Benign

0.024

Sift

Benign

0.76

Sift4G

Benign

0.70

Polyphen

0.0010

Vest4

0.10

MVP

0.25

MPC

0.55

ClinPred

0.025

GERP RS

3.3

Varity_R

0.038

gMVP

0.38

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