NM_003764.4:c.668A>C

Variant names:

• chr6-144187295-A-C
• rs1554294411
• NM_003764.4:c.668A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003764.4(STX11):​c.668A>C​(p.Asp223Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 9.26
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.668A>C	p.Asp223Ala	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.668A>C	p.Asp223Ala	missense	Exon 2 of 2	ENSP00000356540.4	O75558
	STX11	ENST00000698355.1		c.668A>C	p.Asp223Ala	missense	Exon 3 of 3	ENSP00000513678.1	O75558
	STX11	ENST00000698356.1		c.668A>C	p.Asp223Ala	missense	Exon 4 of 4	ENSP00000513679.1	O75558

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial hemophagocytic lymphohistiocytosis 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.3
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.33
Sift	Benign	0.032	D
Sift4G	Uncertain	0.018	D
Polyphen		0.87	P
Vest4		0.41
MutPred		0.64		Gain of MoRF binding (P = 0.0424)
MVP		0.85
MPC		1.2
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.71
gMVP		0.70
Mutation Taster		=69/31	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: rs1554294411; hg19: chr6-144508432;