chr3-120909687-G-C

Variant names:

• chr3-120909687-G-C
• NM_001308330.2:c.109G>C

Variant summary

Our verdict is Likely benign. The variant received -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. 16/22 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
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308330.2. 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
	STXBP5L	NM_001308330.2	MANE Select	c.109G>C	p.Val37Leu	missense	Exon 2 of 27	NP_001295259.1	E9PFI2
	STXBP5L	NM_001348343.2		c.109G>C	p.Val37Leu	missense	Exon 2 of 28	NP_001335272.1	Q9Y2K9-1
	STXBP5L	NM_014980.3		c.109G>C	p.Val37Leu	missense	Exon 2 of 28	NP_055795.1	Q9Y2K9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP5L	ENST00000471454.6	TSL:2 MANE Select	c.109G>C	p.Val37Leu	missense	Exon 2 of 27	ENSP00000420019.1	E9PFI2
	STXBP5L	ENST00000273666.10	TSL:1	c.109G>C	p.Val37Leu	missense	Exon 2 of 28	ENSP00000273666.6	Q9Y2K9-1
	STXBP5L	ENST00000461772.5	TSL:1	n.109G>C		non_coding_transcript_exon	Exon 2 of 9	ENSP00000420642.1	Q9Y2K9-2

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

African (AFR) AF: 0.00 AC: 0 AN: 33348

American (AMR) AF: 0.00 AC: 0 AN: 44286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 85950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111670

Other (OTH) AF: 0.00 AC: 0 AN: 60342

GnomAD4 genome Cov.: 32

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	0.086
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.030
DANN	Benign	0.78
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-2.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.020
Sift	Benign	0.14	T
Sift4G	Uncertain	0.058	T
Polyphen		0.0	B
Vest4		0.099
MutPred		0.19		Gain of sheet (P = 0.0101)
MVP		0.23
MPC		0.18
ClinPred		0.094	T
GERP RS		-10
PromoterAI		-0.074	Neutral
Varity_R		0.078
gMVP		0.25
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

hg19: chr3-120628534;