Genetic Variant NM_001308330.2:c.583A>C (chr3-121115037-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001308330.2(STXBP5L):c.583A>C(p.Met195Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,122 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: 6.9e-7 ( 0 hom. )

Consequence

STXBP5L
NM_001308330.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

Variant links:

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]

STXBP5L links:

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ACMG classification

Classification made for transcript

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 link	c.583A>C	p.Met195Leu	missense_variant	Exon 6 of 27	ENST00000471454.6	NP_001295259.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP5L	ENST00000471454.6 link	c.583A>C	p.Met195Leu	missense_variant	Exon 6 of 27	2	NM_001308330.2	ENSP00000420019.1		E9PFI2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1450122

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720952

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.583A>C (p.M195L) alteration is located in exon 6 (coding exon 5) of the STXBP5L gene. This alteration results from a A to C substitution at nucleotide position 583, causing the methionine (M) at amino acid position 195 to be replaced by a leucine (L). 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

Pathogenic

0.59

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Benign

0.030

T;T;T;T;.;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D

M_CAP

Benign

0.044

MetaRNN

Uncertain

0.57

D;D;D;D;D;D

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.9

L;.;.;.;.;.

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-2.0

N;N;N;N;N;N

REVEL

Benign

0.28

Sift

Benign

0.079

T;T;T;T;T;T

Sift4G

Benign

0.13

T;T;T;T;T;T

Polyphen

0.73

P;P;.;.;.;.

Vest4

0.57

MutPred

0.49

Loss of methylation at K198 (P = 0.0711);Loss of methylation at K198 (P = 0.0711);Loss of methylation at K198 (P = 0.0711);Loss of methylation at K198 (P = 0.0711);Loss of methylation at K198 (P = 0.0711);Loss of methylation at K198 (P = 0.0711);

MVP

0.33

MPC

0.65

ClinPred

0.87

GERP RS

5.6

Varity_R

0.37

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over