rs34282765

Positions:

chr6-144187466-G-A

Variant summary

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

The NM_003764.4(STX11):c.839G>A(p.Cys280Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,612,366 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

STX11
NM_003764.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 9.93

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=0.02099514).

BP6

Variant 6-144187466-G-A is Benign according to our data. Variant chr6-144187466-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 536231.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00197 (300/152282) while in subpopulation AFR AF= 0.00664 (276/41558). AF 95% confidence interval is 0.006. There are 2 homozygotes in gnomad4. There are 127 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 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.839G>A	p.Cys280Tyr	missense_variant	2/2	ENST00000367568.5	NP_003755.2	O75558

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
STX11	ENST00000367568.5 linkuse as main transcript	c.839G>A	p.Cys280Tyr	missense_variant	2/2	1	NM_003764.4	ENSP00000356540.4	O75558
STX11	ENST00000698355.1 linkuse as main transcript	c.839G>A	p.Cys280Tyr	missense_variant	3/3			ENSP00000513678.1	O75558
STX11	ENST00000698356.1 linkuse as main transcript	c.839G>A	p.Cys280Tyr	missense_variant	4/4			ENSP00000513679.1	O75558
STX11	ENST00000698357.1 linkuse as main transcript	c.839G>A	p.Cys280Tyr	missense_variant	2/2			ENSP00000513680.1	O75558

Frequencies

GnomAD3 genomes

AF:

0.00198

AC:

301

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00669

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

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:

0.00

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000551

AC:

136

AN:

247046

Hom.:

AF XY:

0.000357

AC XY:

AN XY:

134418

show subpopulations

Gnomad AFR exome

AF:

0.00656

Gnomad AMR exome

AF:

0.000871

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:

0.0000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000236

AC:

345

AN:

1460084

Hom.:

Cov.:

AF XY:

0.000212

AC XY:

154

AN XY:

726454

show subpopulations

Gnomad4 AFR exome

AF:

0.00735

Gnomad4 AMR exome

AF:

0.000783

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:

0.00000809

Gnomad4 OTH exome

AF:

0.000779

GnomAD4 genome

AF:

0.00197

AC:

300

AN:

152282

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

127

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00664

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000200

Hom.:

Bravo

AF:

0.00233

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000635

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 03, 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 14, 2022

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.76

M_CAP

Benign

0.035

MetaRNN

Benign

0.021

MetaSVM

Uncertain

-0.23

MutationAssessor

Pathogenic

3.2

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-6.2

REVEL

Pathogenic

0.70

Sift

Benign

0.035

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.84

MVP

0.91

MPC

0.63

ClinPred

0.073

GERP RS

5.6

Varity_R

0.73

gMVP

0.80

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