rs1445120718

Variant names:

• chr17-54990825-G-T
• rs1445120718
• NM_178509.6:c.48G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_178509.6(STXBP4):​c.48G>T​(p.Lys16Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: STXBP4 NM_178509.6 missense, splice_region
• Scores: Splicing: ADA: 0.9949
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0540
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178509.6. 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.48G>T	p.Lys16Asn	missense splice_region	Exon 4 of 18	NP_848604.3	Q6ZWJ1-1
	STXBP4	NM_001398481.1		c.48G>T	p.Lys16Asn	missense splice_region	Exon 4 of 18	NP_001385410.1
	STXBP4	NM_001398483.1		c.48G>T	p.Lys16Asn	missense splice_region	Exon 4 of 17	NP_001385412.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP4	ENST00000376352.6	TSL:2 MANE Select	c.48G>T	p.Lys16Asn	missense splice_region	Exon 4 of 18	ENSP00000365530.2	Q6ZWJ1-1
	STXBP4	ENST00000434978.6	TSL:1	c.48G>T	p.Lys16Asn	missense splice_region	Exon 4 of 17	ENSP00000391087.2	E7EPP7
	STXBP4	ENST00000398391.6	TSL:1	c.-52+4559G>T		intron	N/A	ENSP00000381427.2	Q6ZWJ1-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445964 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 719060

African (AFR) AF: 0.00 AC: 0 AN: 32322

American (AMR) AF: 0.00 AC: 0 AN: 40328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25704

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39008

South Asian (SAS) AF: 0.00 AC: 0 AN: 82860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107020

Other (OTH) AF: 0.00 AC: 0 AN: 59750

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.054
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.027
Sift	Uncertain	0.024	D
Sift4G	Benign	0.30	T
Polyphen		0.36	B
Vest4		0.20
MutPred		0.46		Loss of ubiquitination at K16 (P = 0.0071)
MVP		0.41
MPC		0.18
ClinPred		0.32	T
GERP RS		0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.058
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 16

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1445120718; hg19: chr17-53068186;