17-54999351-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_178509.6(STXBP4):c.187C>G(p.Arg63Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R63H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP4 NM_178509.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP4	NM_178509.6	c.187C>G	p.Arg63Gly	missense_variant	5/18	ENST00000376352.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP4	ENST00000376352.6	c.187C>G	p.Arg63Gly	missense_variant	5/18	2	NM_178509.6	P1
STXBP4	ENST00000434978.6	c.187C>G	p.Arg63Gly	missense_variant	5/17	1
STXBP4	ENST00000398391.6	c.-45C>G		5_prime_UTR_variant	4/11	1
STXBP4	ENST00000405898.5	c.187C>G	p.Arg63Gly	missense_variant	4/11	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000227

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

Sep 06, 2022

The c.187C>G (p.R63G) alteration is located in exon 5 (coding exon 3) of the STXBP4 gene. This alteration results from a C to G substitution at nucleotide position 187, causing the arginine (R) at amino acid position 63 to be replaced by a glycine (G). 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	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.014	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.89
MutPred		0.71		Loss of ubiquitination at K65 (P = 0.0742);Loss of ubiquitination at K65 (P = 0.0742);Loss of ubiquitination at K65 (P = 0.0742);
MVP		0.63
MPC		0.74
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.82
gMVP		0.76

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: rs769987070; hg19: chr17-53076712;