3-120909687-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001308330.2(STXBP5L):c.109G>C(p.Val37Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: STXBP5L NM_001308330.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.25

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04216051).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP5L	NM_001308330.2	c.109G>C	p.Val37Leu	missense_variant	2/27	ENST00000471454.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP5L	ENST00000471454.6	c.109G>C	p.Val37Leu	missense_variant	2/27	2	NM_001308330.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460522 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726514

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

The c.109G>C (p.V37L) alteration is located in exon 2 (coding exon 1) of the STXBP5L gene. This alteration results from a G to C substitution at nucleotide position 109, causing the valine (V) at amino acid position 37 to be replaced by a leucine (L). 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	Benign	0.086
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.030
Dann	Benign	0.78
DEOGEN2	Benign	0.012	T;T;T;T;.;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.61	T;T;T;T;T;T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.042	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N;N
REVEL	Benign	0.020
Sift	Benign	0.14	T;T;T;T;T;T;T
Sift4G	Uncertain	0.058	T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;.;.;.;.
Vest4		0.099
MutPred		0.19		Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);
MVP		0.23
MPC		0.18
ClinPred		0.094	T
GERP RS		-10
Varity_R		0.078
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-120628534;