Variant 20-1305812-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001318234.2(SNPH):c.1375A>G(p.Lys459Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,586,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

SNPH
NM_001318234.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.893

Variant links:

Genes affected

SNPH (HGNC:15931): (syntaphilin) Syntaxin-1, synaptobrevin/VAMP, and SNAP25 interact to form the SNARE complex, which is required for synaptic vesicle docking and fusion. The protein encoded by this gene is membrane-associated and inhibits SNARE complex formation by binding free syntaxin-1. Expression of this gene appears to be brain-specific. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

SNPH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03284511).

BS2

High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNPH	NM_001318234.2 linkuse as main transcript	c.1375A>G	p.Lys459Glu	missense_variant	7/7	ENST00000381867.6	NP_001305163.1	O15079-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SNPH	ENST00000381867.6 linkuse as main transcript	c.1375A>G	p.Lys459Glu	missense_variant	7/7	1	NM_001318234.2	ENSP00000371291.1	O15079-2
SNPH	ENST00000614659.1 linkuse as main transcript	c.1375A>G	p.Lys459Glu	missense_variant	4/4	1		ENSP00000479696.1	O15079-2
SNPH	ENST00000381873.7 linkuse as main transcript	c.1243A>G	p.Lys415Glu	missense_variant	6/6	1		ENSP00000371297.3	O15079-1
SNPH	ENST00000649598.1 linkuse as main transcript	c.1342A>G	p.Lys448Glu	missense_variant	6/6			ENSP00000496966.1	A0A3B3IRY9

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000209

AC:

AN:

191038

Hom.:

AF XY:

0.0000192

AC XY:

AN XY:

104350

show subpopulations

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 SAS exome

AF:

0.0000386

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000379

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000105

AC:

AN:

1434126

Hom.:

Cov.:

AF XY:

0.0000127

AC XY:

AN XY:

711264

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:

0.0000121

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000109

Gnomad4 OTH exome

AF:

0.0000337

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000167

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2024

The c.1243A>G (p.K415E) alteration is located in exon 6 (coding exon 4) of the SNPH gene. This alteration results from a A to G substitution at nucleotide position 1243, causing the lysine (K) at amino acid position 415 to be replaced by a glutamic acid (E). 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

0.094

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.079

.;T;.;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.58

T;T;.;T

M_CAP

Benign

0.0064

MetaRNN

Benign

0.033

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

.;N;.;.

PrimateAI

Benign

0.40

PROVEAN

Benign

0.76

.;N;N;.

REVEL

Benign

0.056

Sift

Benign

0.82

.;T;T;.

Sift4G

Benign

1.0

.;T;T;T

Polyphen

0.10, 0.21

.;B;B;B

Vest4

0.15, 0.13, 0.13

MutPred

0.24

.;Loss of ubiquitination at K415 (P = 0.0063);.;.;

MVP

0.082

MPC

0.71

ClinPred

0.048

GERP RS

2.9

Varity_R

0.083

gMVP

0.18

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over