6-144186661-T-G

Position:

• chr6-144186661-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003764.4(STX11):​c.34T>G​(p.Ser12Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STX11 NM_003764.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.202

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05517602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STX11	NM_003764.4	c.34T>G	p.Ser12Ala	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.34T>G	p.Ser12Ala	missense_variant	2/2	1	NM_003764.4	ENSP00000356540.4
STX11	ENST00000698355.1	c.34T>G	p.Ser12Ala	missense_variant	3/3			ENSP00000513678.1
STX11	ENST00000698356.1	c.34T>G	p.Ser12Ala	missense_variant	4/4			ENSP00000513679.1
STX11	ENST00000698357.1	c.34T>G	p.Ser12Ala	missense_variant	2/2			ENSP00000513680.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 16, 2020

This variant has not been reported in the literature in individuals with STX11-related conditions. This sequence change replaces serine with alanine at codon 12 of the STX11 protein (p.Ser12Ala). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and alanine. This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.76	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.023
Sift	Benign	0.36	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.039
MutPred		0.45		Loss of disorder (P = 0.0584);
MVP		0.55
MPC		0.31
ClinPred		0.14	T
GERP RS		3.4
Varity_R		0.033
gMVP		0.26

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: rs1802044955; hg19: chr6-144507798;