3-121152555-G-A

Variant names:

• chr3-121152555-G-A
• rs745597035
• NM_001308330.2:c.748G>A

Variant summary

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

The NM_001308330.2(STXBP5L):​c.748G>A​(p.Asp250Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,447,028 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. D250H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: STXBP5L NM_001308330.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.09
• 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: 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_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.748G>A	p.Asp250Asn	missense	Exon 8 of 27	NP_001295259.1	E9PFI2
	STXBP5L	NM_001348343.2		c.748G>A	p.Asp250Asn	missense	Exon 8 of 28	NP_001335272.1	Q9Y2K9-1
	STXBP5L	NM_014980.3		c.748G>A	p.Asp250Asn	missense	Exon 8 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.748G>A	p.Asp250Asn	missense	Exon 8 of 27	ENSP00000420019.1	E9PFI2
	STXBP5L	ENST00000273666.10	TSL:1	c.748G>A	p.Asp250Asn	missense	Exon 8 of 28	ENSP00000273666.6	Q9Y2K9-1
	STXBP5L	ENST00000461772.5	TSL:1	n.*519G>A		non_coding_transcript_exon	Exon 8 of 9	ENSP00000420642.1	Q9Y2K9-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447028 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 720630

African (AFR) AF: 0.0000306 AC: 1 AN: 32720

American (AMR) AF: 0.00 AC: 0 AN: 42698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25868

East Asian (EAS) AF: 0.00 AC: 0 AN: 39326

South Asian (SAS) AF: 0.00 AC: 0 AN: 85340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52858

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

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102644

Other (OTH) AF: 0.00 AC: 0 AN: 59844

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.2	L
PhyloP100		9.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.27
Sift	Uncertain	0.012	D
Sift4G	Benign	0.29	T
Polyphen		1.0	D
Vest4		0.82
MutPred		0.47		Loss of catalytic residue at D250 (P = 0.064)
MVP		0.51
MPC		0.71
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.44
gMVP		0.35
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs745597035; hg19: chr3-120871402; COSMIC: COSV107264766;