rs146949718

chr6-144187173-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_003764.4(STX11):c.546G>A(p.Glu182=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00273 in 1,613,996 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (33 hom.)
• Consequence: STX11 NM_003764.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.82

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 6-144187173-G-A is Benign according to our data. Variant chr6-144187173-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-144187173-G-A is described in Lovd as [Likely_benign]. Variant chr6-144187173-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00303 (462/152336) while in subpopulation SAS AF= 0.0089 (43/4830). AF 95% confidence interval is 0.00679. There are 3 homozygotes in gnomad4. There are 247 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STX11	NM_003764.4	c.546G>A	p.Glu182=	synonymous_variant	2/2	ENST00000367568.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STX11	ENST00000367568.5	c.546G>A	p.Glu182=	synonymous_variant	2/2	1	NM_003764.4	P1
STX11	ENST00000698355.1	c.546G>A	p.Glu182=	synonymous_variant	3/3			P1
STX11	ENST00000698356.1	c.546G>A	p.Glu182=	synonymous_variant	4/4			P1
STX11	ENST00000698357.1	c.546G>A	p.Glu182=	synonymous_variant	2/2			P1

Frequencies

GnomAD3 genomes AF: 0.00305 AC: 464 AN: 152218 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.00536

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00910

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00257

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00403 AC: 1011 AN: 250888 Hom.: 10 AF XY: 0.00484 AC XY: 657 AN XY: 135710

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.0198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0122

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00295

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00270 AC: 3947 AN: 1461660 Hom.: 33 Cov.: 31 AF XY: 0.00310 AC XY: 2255 AN XY: 727158

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.0204

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0125

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.00165

Gnomad4 OTH exome AF: 0.00450

GnomAD4 genome AF: 0.00303 AC: 462 AN: 152336 Hom.: 3 Cov.: 33 AF XY: 0.00332 AC XY: 247 AN XY: 74494

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.0210

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00890

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00257

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00335 Hom.: 1

Bravo AF: 0.00301

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00551

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Familial hemophagocytic lymphohistiocytosis 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	STX11: BP4, BP7, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	9.0
Dann	Benign	0.61

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

Other links and lift over

dbSNP: rs146949718; hg19: chr6-144508310;