Genetic Variant SNPH:p.Asp194His (chr20-1305017-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BS2

The NM_001318234.2(SNPH):c.580G>C(p.Asp194His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,738 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: 0.0000034 ( 0 hom. )

Consequence

SNPH
NM_001318234.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNPH	NM_001318234.2 link	c.580G>C	p.Asp194His	missense_variant	Exon 7 of 7	ENST00000381867.6	NP_001305163.1	O15079-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SNPH	ENST00000381867.6 link	c.580G>C	p.Asp194His	missense_variant	Exon 7 of 7	1	NM_001318234.2	ENSP00000371291.1	O15079-2
SNPH	ENST00000614659.1 link	c.580G>C	p.Asp194His	missense_variant	Exon 4 of 4	1		ENSP00000479696.1	O15079-2
SNPH	ENST00000381873.7 link	c.448G>C	p.Asp150His	missense_variant	Exon 6 of 6	1		ENSP00000371297.3	O15079-1
SNPH	ENST00000649598.1 link	c.547G>C	p.Asp183His	missense_variant	Exon 6 of 6			ENSP00000496966.1	A0A3B3IRY9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53278

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 29, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.448G>C (p.D150H) alteration is located in exon 6 (coding exon 4) of the SNPH gene. This alteration results from a G to C substitution at nucleotide position 448, causing the aspartic acid (D) at amino acid position 150 to be replaced by a histidine (H). 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

0.90

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

.;D;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;.;D

M_CAP

Benign

0.079

MetaRNN

Uncertain

0.64

D;D;D;D

MetaSVM

Uncertain

0.081

MutationAssessor

Uncertain

2.2

.;M;.;.

PhyloP100

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.9

.;D;D;.

REVEL

Uncertain

0.48

Sift

Uncertain

0.0010

.;D;D;.

Sift4G

Uncertain

0.0040

.;D;D;D

Polyphen

1.0

.;D;D;D

Vest4

0.78, 0.78

MutPred

0.20

.;Loss of ubiquitination at K153 (P = 0.0435);.;.;

MVP

0.74

MPC

1.5

ClinPred

0.98

GERP RS

4.4

Varity_R

0.57

gMVP

0.59

Mutation Taster

=50/50

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over