6-144186648-ACTT-A

Position:

• chr6-144186648-ACTT-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PM4_Supporting BS1_Supporting

The NM_003764.4(STX11):​c.24_26del​(p.Leu9del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: STX11 NM_003764.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.45

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_003764.4. Strenght limited to Supporting due to length of the change: 1aa.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000276 (42/152214) while in subpopulation NFE AF= 0.000529 (36/68036). AF 95% confidence interval is 0.000392. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STX11	NM_003764.4	c.24_26del	p.Leu9del	inframe_deletion	2/2	ENST00000367568.5	NP_003755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STX11	ENST00000367568.5	c.24_26del	p.Leu9del	inframe_deletion	2/2	1	NM_003764.4	ENSP00000356540	P1
STX11	ENST00000698355.1	c.24_26del	p.Leu9del	inframe_deletion	3/3			ENSP00000513678	P1
STX11	ENST00000698356.1	c.24_26del	p.Leu9del	inframe_deletion	4/4			ENSP00000513679	P1
STX11	ENST00000698357.1	c.24_26del	p.Leu9del	inframe_deletion	2/2			ENSP00000513680	P1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000211 AC: 53 AN: 251272 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135900

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000426 AC: 622 AN: 1461804 Hom.: 0 AF XY: 0.000407 AC XY: 296 AN XY: 727212

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000526

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74370

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.000254 Hom.: 0

Bravo AF: 0.000238

EpiCase AF: 0.000436

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2022

This variant, c.24_26del, results in the deletion of 1 amino acid(s) of the STX11 protein (p.Leu9del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs760492745, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with STX11-related conditions. ClinVar contains an entry for this variant (Variation ID: 355597). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Familial hemophagocytic lymphohistiocytosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 22, 2017

- -

Computational scores

Source: dbNSFP v4.3

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: rs760492745; hg19: chr6-144507785;