17-55073044-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_178509.6(STXBP4):c.1156G>C(p.Ala386Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,464 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: STXBP4 NM_178509.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92

Genes affected

STXBP4 (HGNC:19694): (syntaxin binding protein 4) Enables syntaxin binding activity. Involved in several processes, including positive regulation of cell cycle G1/S phase transition; positive regulation of keratinocyte proliferation; and protein stabilization. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP4	NM_178509.6	c.1156G>C	p.Ala386Pro	missense_variant	13/18	ENST00000376352.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP4	ENST00000376352.6	c.1156G>C	p.Ala386Pro	missense_variant	13/18	2	NM_178509.6	P1
STXBP4	ENST00000434978.6	c.1090G>C	p.Ala364Pro	missense_variant	12/17	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461464 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727034

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2022

The c.1156G>C (p.A386P) alteration is located in exon 13 (coding exon 11) of the STXBP4 gene. This alteration results from a G to C substitution at nucleotide position 1156, causing the alanine (A) at amino acid position 386 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.12
Sift	Benign	0.073	T;T
Sift4G	Benign	0.070	T;T
Polyphen		1.0	D;D
Vest4		0.73
MutPred		0.22		Loss of ubiquitination at K385 (P = 0.0952);.;
MVP		0.76
MPC		0.62
ClinPred		0.81	D
GERP RS		5.6
Varity_R		0.66
gMVP		0.45

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: rs767763765; hg19: chr17-53150405;