rs45574234

Positions:

• chr6-144187426-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003764.4(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (52 hom.)
• Consequence: STX11 NM_003764.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.74

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]

ACMG classification

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	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	UniProt
STX11	ENST00000367568.5	c.799G>A	p.Val267Met	missense_variant	2/2	1	NM_003764.4	ENSP00000356540.4
STX11	ENST00000698355.1	c.799G>A	p.Val267Met	missense_variant	3/3			ENSP00000513678.1
STX11	ENST00000698356.1	c.799G>A	p.Val267Met	missense_variant	4/4			ENSP00000513679.1
STX11	ENST00000698357.1	c.799G>A	p.Val267Met	missense_variant	2/2			ENSP00000513680.1

Frequencies

GnomAD3 genomes AF: 0.00543 AC: 826 AN: 152182 Hom.: 11 Cov.: 32

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.: 6 AF XY: 0.00538 AC XY: 722 AN XY: 134178

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.: 52 Cov.: 31 AF XY: 0.00700 AC XY: 5081 AN XY: 726188

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.: 11 Cov.: 32 AF XY: 0.00536 AC XY: 399 AN XY: 74472

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.: 7

Bravo AF: 0.00543

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00919 AC: 79

ExAC AF: 0.00549 AC: 667

Asia WGS AF: 0.00144 AC: 6 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

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	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.26
Sift	Benign	0.036	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.089
MVP		0.72
MPC		1.0
ClinPred		0.012	T
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

Other links and lift over

dbSNP: rs45574234; hg19: chr6-144508563;