6-144187216-G-A

Variant names:

• chr6-144187216-G-A
• rs141499372
• NM_003764.4:c.589G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_003764.4(STX11):​c.589G>A​(p.Val197Met) variant causes a missense change. The variant allele was found at a frequency of 0.000396 in 1,613,968 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V197L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00039 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (1 hom.)
• Consequence: STX11 NM_003764.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 6.87
• Publications: 8 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: Labcorp Genetics (formerly Invitae), ClinGen
• hereditary hemophagocytic lymphohistiocytosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015579969).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000394 (60/152378) while in subpopulation SAS AF = 0.00228 (11/4832). AF 95% confidence interval is 0.00128. There are 1 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STX11	NM_003764.4	MANE Select	c.589G>A	p.Val197Met	missense	Exon 2 of 2	NP_003755.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STX11	ENST00000367568.5	TSL:1 MANE Select	c.589G>A	p.Val197Met	missense	Exon 2 of 2	ENSP00000356540.4
	STX11	ENST00000698355.1		c.589G>A	p.Val197Met	missense	Exon 3 of 3	ENSP00000513678.1
	STX11	ENST00000698356.1		c.589G>A	p.Val197Met	missense	Exon 4 of 4	ENSP00000513679.1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152260 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000479 AC: 120 AN: 250760 AF XY: 0.000678

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000353

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000396 AC: 579 AN: 1461590 Hom.: 1 Cov.: 31 AF XY: 0.000487 AC XY: 354 AN XY: 727138

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00267 AC: 230 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53200

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5766

European-Non Finnish (NFE) AF: 0.000249 AC: 277 AN: 1111958

Other (OTH) AF: 0.000547 AC: 33 AN: 60384

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152378 Hom.: 1 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74520

African (AFR) AF: 0.0000481 AC: 2 AN: 41590

American (AMR) AF: 0.00157 AC: 24 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4832

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000322 Hom.: 1

Bravo AF: 0.000276

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000428 AC: 52

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000771

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Familial hemophagocytic lymphohistiocytosis 4 (3)
-	1	-	Autoinflammatory syndrome (1)
-	1	-	not provided (1)
-	-	1	STX11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.076
Sift	Benign	0.052	T
Sift4G	Benign	0.089	T
Polyphen		0.89	P
Vest4		0.31
MVP		0.49
MPC		0.72
ClinPred		0.074	T
GERP RS		4.3
Varity_R		0.26
gMVP		0.35
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs141499372; hg19: chr6-144508353; COSMIC: COSV62448973;