rs1947171919

Variant names:

• chr3-121041722-T-A
• rs1947171919
• NM_001308330.2:c.310T>A

Your query was ambiguous. Multiple possible variants found:

• chr3-121041722-T-A
• chr3-121041722-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001308330.2(STXBP5L):​c.310T>A​(p.Cys104Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,612,590 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: STXBP5L NM_001308330.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.47
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771

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.310T>A	p.Cys104Ser	missense	Exon 4 of 27	NP_001295259.1	E9PFI2
	STXBP5L	NM_001348343.2		c.310T>A	p.Cys104Ser	missense	Exon 4 of 28	NP_001335272.1	Q9Y2K9-1
	STXBP5L	NM_014980.3		c.310T>A	p.Cys104Ser	missense	Exon 4 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.310T>A	p.Cys104Ser	missense	Exon 4 of 27	ENSP00000420019.1	E9PFI2
	STXBP5L	ENST00000273666.10	TSL:1	c.310T>A	p.Cys104Ser	missense	Exon 4 of 28	ENSP00000273666.6	Q9Y2K9-1
	STXBP5L	ENST00000461772.5	TSL:1	n.*81T>A		non_coding_transcript_exon	Exon 4 of 9	ENSP00000420642.1	Q9Y2K9-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460480 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726554

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111088

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74288

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.23
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.085
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.1	L
PhyloP100		6.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.32
Sift	Benign	0.038	D
Sift4G	Benign	0.24	T
Polyphen		0.010	B
Vest4		0.91
MutPred		0.59		Gain of disorder (P = 0.0058)
MVP		0.84
MPC		0.23
ClinPred		0.91	D
GERP RS		5.2
Varity_R		0.55
gMVP		0.54
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1947171919; hg19: chr3-120760569;