rs45574234

Positions:

chr6-144187426-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000367568.5(STX11):c.799G>A(p.Val267Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0069 in 1,611,770 control chromosomes in the GnomAD database, including 63 homozygotes. 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V267V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0054 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 52 hom. )

Consequence

STX11
ENST00000367568.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.74

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009943932).

BP6

Variant 6-144187426-G-A is Benign according to our data. Variant chr6-144187426-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-144187426-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00542 (826/152300) while in subpopulation NFE AF= 0.00908 (618/68030). AF 95% confidence interval is 0.00849. There are 11 homozygotes in gnomad4. There are 399 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STX11	NM_003764.4 linkuse as main transcript	c.799G>A	p.Val267Met	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.799G>A	p.Val267Met	missense_variant	2/2	1	NM_003764.4	ENSP00000356540	P1
STX11	ENST00000698355.1 linkuse as main transcript	c.799G>A	p.Val267Met	missense_variant	3/3			ENSP00000513678	P1
STX11	ENST00000698356.1 linkuse as main transcript	c.799G>A	p.Val267Met	missense_variant	4/4			ENSP00000513679	P1
STX11	ENST00000698357.1 linkuse as main transcript	c.799G>A	p.Val267Met	missense_variant	2/2			ENSP00000513680	P1

Frequencies

GnomAD3 genomes

AF:

0.00543

AC:

826

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00609

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00908

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00532

AC:

1314

AN:

247122

Hom.:

AF XY:

0.00538

AC XY:

722

AN XY:

134178

show subpopulations

Gnomad AFR exome

AF:

0.00138

Gnomad AMR exome

AF:

0.00452

Gnomad ASJ exome

AF:

0.00229

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.00314

Gnomad FIN exome

AF:

0.00314

Gnomad NFE exome

AF:

0.00810

Gnomad OTH exome

AF:

0.00740

GnomAD4 exome

AF:

0.00705

AC:

10288

AN:

1459470

Hom.:

Cov.:

AF XY:

0.00700

AC XY:

5081

AN XY:

726188

show subpopulations

Gnomad4 AFR exome

AF:

0.00164

Gnomad4 AMR exome

AF:

0.00474

Gnomad4 ASJ exome

AF:

0.00260

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00321

Gnomad4 FIN exome

AF:

0.00329

Gnomad4 NFE exome

AF:

0.00817

Gnomad4 OTH exome

AF:

0.00672

GnomAD4 genome

AF:

0.00542

AC:

826

AN:

152300

Hom.:

Cov.:

AF XY:

0.00536

AC XY:

399

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.00608

Gnomad4 ASJ

AF:

0.00260

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00292

Gnomad4 NFE

AF:

0.00908

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00739

Hom.:

Bravo

AF:

0.00543

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00919

AC:

ExAC

AF:

0.00549

AC:

667

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00703

EpiControl

AF:

0.00735

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 4

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 25, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	STX11: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2020	This variant is associated with the following publications: (PMID: 24524345, 30290665, 28399723) -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2022	Variant summary: STX11 c.799G>A (p.Val267Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0053 in 247122 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in STX11 causing Familial Hemophagocytic Lymphohistiocytosis phenotype (0.0005), strongly suggesting that the variant is benign. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=2) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

Autoinflammatory syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.78

M_CAP

Benign

0.021

MetaRNN

Benign

0.0099

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

0.98

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.7

REVEL

Benign

0.26

Sift

Benign

0.036

Sift4G

Uncertain

0.0080

Polyphen

0.99

Vest4

0.089

MVP

0.72

MPC

1.0

ClinPred

0.012

GERP RS

2.9

Varity_R

0.12

gMVP

0.30

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