17-54999625-G-C

Position:

• chr17-54999625-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The ENST00000398391.6(STXBP4):​c.57-1G>C variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP4 ENST00000398391.6 splice_acceptor
• Scores: Splicing: ADA: 0.00003773
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.24

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.29268292 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.1, offset of 6, new splice context is: tgatttctttttactactAGgtt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP4	NM_178509.6	c.288-7G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000376352.6	NP_848604.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP4	ENST00000398391.6	c.57-1G>C		splice_acceptor_variant		1		ENSP00000381427
STXBP4	ENST00000376352.6	c.288-7G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_178509.6	ENSP00000365530	P1
STXBP4	ENST00000434978.6	c.288-7G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000391087
STXBP4	ENST00000405898.5	c.288-7G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000385944

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.83
DANN	Benign	0.71
Eigen	Benign	0.11
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.078	N
MutationTaster	Benign	1.0	P;P;P;P;P
GERP RS		2.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
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: rs11658717; hg19: chr17-53076986;