rs483352901

Variant names:

• chr6-144186996-AGTGGCGC-TGG
• rs483352901
• NM_003764.4:c.369_376delAGTGGCGCinsTGG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003764.4(STX11):​c.369_376delAGTGGCGCinsTGG​(p.Val124GlyfsTer60) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A123A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STX11 NM_003764.4 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.58
• Publications: 4 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 22 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-144186996-AGTGGCGC-TGG is Pathogenic according to our data. Variant chr6-144186996-AGTGGCGC-TGG is described in ClinVar as Pathogenic. ClinVar VariationId is 5263.Status of the report is criteria_provided_single_submitter, 1 stars.

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.369_376delAGTGGCGCinsTGG	p.Val124GlyfsTer60	frameshift missense	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.369_376delAGTGGCGCinsTGG	p.Val124GlyfsTer60	frameshift missense	Exon 2 of 2	ENSP00000356540.4	O75558
	STX11	ENST00000698355.1		c.369_376delAGTGGCGCinsTGG	p.Val124GlyfsTer60	frameshift missense	Exon 3 of 3	ENSP00000513678.1	O75558
	STX11	ENST00000698356.1		c.369_376delAGTGGCGCinsTGG	p.Val124GlyfsTer60	frameshift missense	Exon 4 of 4	ENSP00000513679.1	O75558

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Familial hemophagocytic lymphohistiocytosis 4 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.6
Mutation Taster		=10/190	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs483352901; hg19: chr6-144508133;