chr17-54990899-G-T

Variant names:

• chr17-54990899-G-T
• rs778811461
• NM_178509.6:c.122G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_178509.6(STXBP4):​c.122G>T​(p.Arg41Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,654 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R41Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: STXBP4 NM_178509.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.03
• 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 2 ACMG points.

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

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.122G>T	p.Arg41Leu	missense	Exon 4 of 18	NP_848604.3	Q6ZWJ1-1
	STXBP4	NM_001398481.1		c.122G>T	p.Arg41Leu	missense	Exon 4 of 18	NP_001385410.1
	STXBP4	NM_001398483.1		c.122G>T	p.Arg41Leu	missense	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.122G>T	p.Arg41Leu	missense	Exon 4 of 18	ENSP00000365530.2	Q6ZWJ1-1
	STXBP4	ENST00000434978.6	TSL:1	c.122G>T	p.Arg41Leu	missense	Exon 4 of 17	ENSP00000391087.2	E7EPP7
	STXBP4	ENST00000398391.6	TSL:1	c.-52+4633G>T		intron	N/A	ENSP00000381427.2	Q6ZWJ1-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451654 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722036

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32640

American (AMR) AF: 0.00 AC: 0 AN: 42188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25916

East Asian (EAS) AF: 0.00 AC: 0 AN: 39186

South Asian (SAS) AF: 0.00 AC: 0 AN: 84340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108424

Other (OTH) AF: 0.00 AC: 0 AN: 59948

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.050	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.28
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.39		Gain of sheet (P = 0.1539)
MVP		0.66
MPC		0.71
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs778811461; hg19: chr17-53068260;