3-121152529-A-G

Variant names:

• chr3-121152529-A-G
• rs1259325673
• NM_001308330.2:c.722A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001308330.2(STXBP5L):​c.722A>G​(p.Lys241Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,810 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: STXBP5L NM_001308330.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.47

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP5L	NM_001308330.2	c.722A>G	p.Lys241Arg	missense_variant	Exon 8 of 27	ENST00000471454.6	NP_001295259.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP5L	ENST00000471454.6	c.722A>G	p.Lys241Arg	missense_variant	Exon 8 of 27	2	NM_001308330.2	ENSP00000420019.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000816 AC: 2 AN: 245156 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133322

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456810 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 724934

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000458

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: 9.01e-7

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

May 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.722A>G (p.K241R) alteration is located in exon 8 (coding exon 7) of the STXBP5L gene. This alteration results from a A to G substitution at nucleotide position 722, causing the lysine (K) at amino acid position 241 to be replaced by an arginine (R). 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	0.10
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;T;T;.;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.49	T;T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.1	L;.;.;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.5	N;N;D;D;D;N
REVEL	Benign	0.21
Sift	Benign	0.089	T;T;T;T;T;T
Sift4G	Uncertain	0.0080	D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;.
Vest4		0.47
MutPred		0.43		Loss of ubiquitination at K241 (P = 0.0192);Loss of ubiquitination at K241 (P = 0.0192);Loss of ubiquitination at K241 (P = 0.0192);Loss of ubiquitination at K241 (P = 0.0192);Loss of ubiquitination at K241 (P = 0.0192);Loss of ubiquitination at K241 (P = 0.0192);
MVP		0.33
MPC		0.52
ClinPred		0.88	D
GERP RS		5.4
Varity_R		0.31
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1259325673; hg19: chr3-120871376;