chr17-54999625-G-A

Variant names:

• chr17-54999625-G-A
• rs11658717
• NM_178509.6:c.288-7G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PVS1_Strong BA1

The NM_001398481.1(STXBP4):​c.288-1G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.723 in 1,608,732 control chromosomes in the GnomAD database, including 423,129 homozygotes. 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: 𝑓 0.72 (39303 hom., cov: 32)
  • Exomes 𝑓: 0.72 (383826 hom.)
• Consequence: STXBP4 NM_001398481.1 splice_acceptor, intron
• Scores: Splicing: ADA: 0.0003532
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.24
• Publications: 29 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.13009593 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.3, offset of 6, new splice context is: tgatttctttttaatactAGgtt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.886 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001398481.1. 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
	STXBP4	NM_178509.6	MANE Select	c.288-7G>A		splice_region intron	N/A	NP_848604.3
	STXBP4	NM_001398481.1		c.288-1G>A		splice_acceptor intron	N/A	NP_001385410.1
	STXBP4	NM_001398483.1		c.288-7G>A		splice_region intron	N/A	NP_001385412.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP4	ENST00000376352.6	TSL:2 MANE Select	c.288-7G>A		splice_region intron	N/A	ENSP00000365530.2
	STXBP4	ENST00000434978.6	TSL:1	c.288-7G>A		splice_region intron	N/A	ENSP00000391087.2
	STXBP4	ENST00000398391.6	TSL:1	c.57-1G>A		splice_acceptor intron	N/A	ENSP00000381427.2

Frequencies

GnomAD3 genomes AF: 0.717 AC: 108872 AN: 151930 Hom.: 39256 Cov.: 32

Gnomad AFR AF: 0.660

Gnomad AMI AF: 0.854

Gnomad AMR AF: 0.766

Gnomad ASJ AF: 0.756

Gnomad EAS AF: 0.908

Gnomad SAS AF: 0.825

Gnomad FIN AF: 0.726

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.713

Gnomad OTH AF: 0.699

GnomAD2 exomes AF: 0.757 AC: 187246 AN: 247348 AF XY: 0.757

Gnomad AFR exome AF: 0.652

Gnomad AMR exome AF: 0.843

Gnomad ASJ exome AF: 0.760

Gnomad EAS exome AF: 0.894

Gnomad FIN exome AF: 0.726

Gnomad NFE exome AF: 0.716

Gnomad OTH exome AF: 0.739

GnomAD4 exome AF: 0.724 AC: 1054201 AN: 1456684 Hom.: 383826 Cov.: 33 AF XY: 0.727 AC XY: 526723 AN XY: 724752

African (AFR) AF: 0.656 AC: 21773 AN: 33204

American (AMR) AF: 0.836 AC: 36998 AN: 44260

Ashkenazi Jewish (ASJ) AF: 0.761 AC: 19757 AN: 25962

East Asian (EAS) AF: 0.928 AC: 36732 AN: 39566

South Asian (SAS) AF: 0.811 AC: 69410 AN: 85576

European-Finnish (FIN) AF: 0.723 AC: 38524 AN: 53314

Middle Eastern (MID) AF: 0.750 AC: 4307 AN: 5746

European-Non Finnish (NFE) AF: 0.706 AC: 783092 AN: 1108874

Other (OTH) AF: 0.725 AC: 43608 AN: 60182

GnomAD4 genome AF: 0.717 AC: 108983 AN: 152048 Hom.: 39303 Cov.: 32 AF XY: 0.721 AC XY: 53555 AN XY: 74308

African (AFR) AF: 0.661 AC: 27391 AN: 41458

American (AMR) AF: 0.766 AC: 11710 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.756 AC: 2625 AN: 3472

East Asian (EAS) AF: 0.908 AC: 4701 AN: 5178

South Asian (SAS) AF: 0.826 AC: 3976 AN: 4816

European-Finnish (FIN) AF: 0.726 AC: 7671 AN: 10564

Middle Eastern (MID) AF: 0.752 AC: 221 AN: 294

European-Non Finnish (NFE) AF: 0.713 AC: 48432 AN: 67954

Other (OTH) AF: 0.699 AC: 1477 AN: 2112

Alfa AF: 0.719 Hom.: 110272

Bravo AF: 0.716

TwinsUK AF: 0.719 AC: 2667

ALSPAC AF: 0.710 AC: 2738

ESP6500AA AF: 0.649 AC: 2858

ESP6500EA AF: 0.715 AC: 6148

ExAC AF: 0.754 AC: 91471

Asia WGS AF: 0.847 AC: 2942 AN: 3478

EpiCase AF: 0.711

EpiControl AF: 0.714

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.0
DANN	Benign	0.73
Eigen	Benign	0.11
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.0010	N
PhyloP100		1.2
GERP RS		2.4
PromoterAI		-0.0033	Neutral
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00035
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: rs11658717; hg19: chr17-53076986;