3-120955001-T-G

Variant names:

• chr3-120955001-T-G
• rs1435838523
• NM_001308330.2:c.251T>G

Variant summary

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

The NM_001308330.2(STXBP5L):​c.251T>G​(p.Ile84Ser) variant causes a missense change involving the alteration of a 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP5L NM_001308330.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.40

Genes affected

STXBP5L (HGNC:30757): (syntaxin binding protein 5L) The protein encoded by this gene is similar to syntaxin-binding protein 5 and contains ten N-terminal WD40 repeats, four variable region WD40 repeats, and a C-terminal R-SNARE domain. Studies of the orthologous proteins in mouse and rat have shown that the encoded protein may inhibit exocytosis in neurosecretory cells, and may negatively regulate the secretion of insulin. A missense variant in this gene is likely the cause of an infantile-onset neurodegenerative disorder diagnosed in two siblings of consanguineous parents. [provided by RefSeq, Jan 2017]

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, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP5L	NM_001308330.2	c.251T>G	p.Ile84Ser	missense_variant	Exon 3 of 27	ENST00000471454.6	NP_001295259.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP5L	ENST00000471454.6	c.251T>G	p.Ile84Ser	missense_variant	Exon 3 of 27	2	NM_001308330.2	ENSP00000420019.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.251T>G (p.I84S) alteration is located in exon 3 (coding exon 2) of the STXBP5L gene. This alteration results from a T to G substitution at nucleotide position 251, causing the isoleucine (I) at amino acid position 84 to be replaced by a serine (S). 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	0.97
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T;T;T;.;.;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		0.97	D;P;.;.;.;.;.
Vest4		0.98
MutPred		0.57		Gain of ubiquitination at K83 (P = 0.039);Gain of ubiquitination at K83 (P = 0.039);Gain of ubiquitination at K83 (P = 0.039);Gain of ubiquitination at K83 (P = 0.039);Gain of ubiquitination at K83 (P = 0.039);Gain of ubiquitination at K83 (P = 0.039);Gain of ubiquitination at K83 (P = 0.039);
MVP		0.96
MPC		0.27
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.78
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1435838523; hg19: chr3-120673848;