11-59773224-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004177.5(STX3):c.44A>G(p.Gln15Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00447 in 1,614,176 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (30 hom.)
• Consequence: STX3 NM_004177.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.95

Genes affected

STX3 (HGNC:11438): (syntaxin 3) The gene is a member of the syntaxin family. The encoded protein is targeted to the apical membrane of epithelial cells where it forms clusters and is important in establishing and maintaining polarity necessary for protein trafficking involving vesicle fusion and exocytosis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053287446).
• BP6: Variant 11-59773224-A-G is Benign according to our data. Variant chr11-59773224-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 787544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-59773224-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00509 (776/152350) while in subpopulation AFR AF= 0.00734 (305/41580). AF 95% confidence interval is 0.00666. There are 5 homozygotes in gnomad4. There are 372 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STX3	NM_004177.5	c.44A>G	p.Gln15Arg	missense_variant	2/11	ENST00000337979.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STX3	ENST00000337979.9	c.44A>G	p.Gln15Arg	missense_variant	2/11	1	NM_004177.5	A1

Frequencies

GnomAD3 genomes AF: 0.00502 AC: 764 AN: 152232 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00707

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00451

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00335 AC: 843 AN: 251368 Hom.: 2 AF XY: 0.00310 AC XY: 421 AN XY: 135856

Gnomad AFR exome AF: 0.00708

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00582

Gnomad NFE exome AF: 0.00419

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00440 AC: 6434 AN: 1461826 Hom.: 30 Cov.: 30 AF XY: 0.00430 AC XY: 3127 AN XY: 727210

Gnomad4 AFR exome AF: 0.0109

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.00318

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000487

Gnomad4 FIN exome AF: 0.00524

Gnomad4 NFE exome AF: 0.00477

Gnomad4 OTH exome AF: 0.00431

GnomAD4 genome AF: 0.00509 AC: 776 AN: 152350 Hom.: 5 Cov.: 32 AF XY: 0.00499 AC XY: 372 AN XY: 74516

Gnomad4 AFR AF: 0.00734

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00574

Gnomad4 NFE AF: 0.00451

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00447 Hom.: 3

Bravo AF: 0.00470

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.00431 AC: 37

ExAC AF: 0.00322 AC: 391

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00442

EpiControl AF: 0.00539

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	STX3: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	20
Dann	Benign	0.93
DEOGEN2	Benign	0.050	T;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.050
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T;T;T
MetaRNN	Benign	0.0053	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.;L
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.85	N;.;N
REVEL	Benign	0.036
Sift	Benign	0.34	T;.;T
Sift4G	Benign	0.46	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.38
MVP		0.67
MPC		0.098
ClinPred		0.021	T
GERP RS		5.2
Varity_R		0.20
gMVP		0.24

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: rs2229915; hg19: chr11-59540697; COSMIC: COSV105176476;