6-144187456-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003764.4(STX11):c.829A>G(p.Thr277Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0069 in 1,611,902 control chromosomes in the GnomAD database, including 628 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T277T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.035 (317 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (311 hom.)
• Consequence: STX11 NM_003764.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.55

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016197562).
• BP6: Variant 6-144187456-A-G is Benign according to our data. Variant chr6-144187456-A-G is described in ClinVar as [Benign]. Clinvar id is 259164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-144187456-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STX11	NM_003764.4	c.829A>G	p.Thr277Ala	missense_variant	2/2	ENST00000367568.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STX11	ENST00000367568.5	c.829A>G	p.Thr277Ala	missense_variant	2/2	1	NM_003764.4	P1
STX11	ENST00000698355.1	c.829A>G	p.Thr277Ala	missense_variant	3/3			P1
STX11	ENST00000698356.1	c.829A>G	p.Thr277Ala	missense_variant	4/4			P1
STX11	ENST00000698357.1	c.829A>G	p.Thr277Ala	missense_variant	2/2			P1

Frequencies

GnomAD3 genomes AF: 0.0349 AC: 5298 AN: 151704 Hom.: 315 Cov.: 33

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000854

Gnomad OTH AF: 0.0315

GnomAD3 exomes AF: 0.00919 AC: 2270 AN: 247048 Hom.: 125 AF XY: 0.00685 AC XY: 920 AN XY: 134330

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.00688

Gnomad ASJ exome AF: 0.00490

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000840

Gnomad OTH exome AF: 0.00759

GnomAD4 exome AF: 0.00398 AC: 5816 AN: 1460080 Hom.: 311 Cov.: 31 AF XY: 0.00353 AC XY: 2567 AN XY: 726434

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.00769

Gnomad4 ASJ exome AF: 0.00505

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000579

Gnomad4 NFE exome AF: 0.000535

Gnomad4 OTH exome AF: 0.00852

GnomAD4 genome AF: 0.0350 AC: 5308 AN: 151822 Hom.: 317 Cov.: 33 AF XY: 0.0340 AC XY: 2521 AN XY: 74210

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.0119

Gnomad4 ASJ AF: 0.00606

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.0000948

Gnomad4 NFE AF: 0.000854

Gnomad4 OTH AF: 0.0312

Alfa AF: 0.00416 Hom.: 46

Bravo AF: 0.0390

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.117 AC: 517

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.0111 AC: 1346

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 4 Benign:2

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	15
Dann	Benign	0.93
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.98	P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.057
Sift	Benign	0.14	T
Sift4G	Benign	0.77	T
Polyphen		0.0010	B
Vest4		0.030
MPC		0.36
ClinPred		0.0077	T
GERP RS		1.9
Varity_R		0.040
gMVP		0.37

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: rs9496891; hg19: chr6-144508593;