rs146949718

Variant names:

• chr6-144187173-G-A
• rs146949718
• NM_003764.4:c.546G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_003764.4(STX11):​c.546G>A​(p.Glu182Glu) 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:8
• Conservation: PhyloP100: 5.82
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• familial hemophagocytic lymphohistiocytosis 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hereditary hemophagocytic lymphohistiocytosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 259162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003764.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STX11	NM_003764.4	MANE Select	c.546G>A	p.Glu182Glu	synonymous	Exon 2 of 2	NP_003755.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STX11	ENST00000367568.5	TSL:1 MANE Select	c.546G>A	p.Glu182Glu	synonymous	Exon 2 of 2	ENSP00000356540.4	O75558
	STX11	ENST00000698355.1		c.546G>A	p.Glu182Glu	synonymous	Exon 3 of 3	ENSP00000513678.1	O75558
	STX11	ENST00000698356.1		c.546G>A	p.Glu182Glu	synonymous	Exon 4 of 4	ENSP00000513679.1	O75558

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

GnomAD2 exomes AF: 0.00403 AC: 1011 AN: 250888 AF XY: 0.00484

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 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

African (AFR) AF: 0.000269 AC: 9 AN: 33478

American (AMR) AF: 0.00215 AC: 96 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 534 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0125 AC: 1075 AN: 86258

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53240

Middle Eastern (MID) AF: 0.0208 AC: 120 AN: 5768

European-Non Finnish (NFE) AF: 0.00165 AC: 1839 AN: 1111980

Other (OTH) AF: 0.00450 AC: 272 AN: 60386

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

African (AFR) AF: 0.000385 AC: 16 AN: 41576

American (AMR) AF: 0.00536 AC: 82 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00890 AC: 43 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00257 AC: 175 AN: 68034

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00293 Hom.: 1

Bravo AF: 0.00301

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00551

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Familial hemophagocytic lymphohistiocytosis 4 (2)
-	-	2	not specified (2)
-	-	1	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.0
DANN	Benign	0.61
PhyloP100		5.8
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs146949718; hg19: chr6-144508310;