NM_001308330.2:c.412T>C

Variant names:

• chr3-121045477-T-C
• rs1376773241
• NM_001308330.2:c.412T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_001308330.2(STXBP5L):​c.412T>C​(p.Trp138Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,072 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: STXBP5L NM_001308330.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.94
• Publications: 1 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 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• BS2: High AC in GnomAdExome4 at 6 AD gene.

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.412T>C	p.Trp138Arg	missense	Exon 5 of 27	NP_001295259.1	E9PFI2
	STXBP5L	NM_001348343.2		c.412T>C	p.Trp138Arg	missense	Exon 5 of 28	NP_001335272.1	Q9Y2K9-1
	STXBP5L	NM_014980.3		c.412T>C	p.Trp138Arg	missense	Exon 5 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.412T>C	p.Trp138Arg	missense	Exon 5 of 27	ENSP00000420019.1	E9PFI2
	STXBP5L	ENST00000273666.10	TSL:1	c.412T>C	p.Trp138Arg	missense	Exon 5 of 28	ENSP00000273666.6	Q9Y2K9-1
	STXBP5L	ENST00000461772.5	TSL:1	n.*183T>C		non_coding_transcript_exon	Exon 5 of 9	ENSP00000420642.1	Q9Y2K9-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248704 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461072 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726818

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111528

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.87		Gain of disorder (P = 0.006)
MVP		0.73
MPC		0.99
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.95
gMVP		0.92
Mutation Taster		=26/74	disease causing

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

dbSNP: rs1376773241; hg19: chr3-120764324;