Genetic Variant SNCA:c.307-32740A>G (chr4-89762017-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000345.4(SNCA):c.307-32740A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.813 in 152,148 control chromosomes in the GnomAD database, including 51,187 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.81 ( 51187 hom., cov: 31)

Consequence

SNCA
NM_000345.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.08

Publications

10 publications found

Variant links:

Genes affected

SNCA (HGNC:11138): (synuclein alpha) Alpha-synuclein is a member of the synuclein family, which also includes beta- and gamma-synuclein. Synucleins are abundantly expressed in the brain and alpha- and beta-synuclein inhibit phospholipase D2 selectively. SNCA may serve to integrate presynaptic signaling and membrane trafficking. Defects in SNCA have been implicated in the pathogenesis of Parkinson disease. SNCA peptides are a major component of amyloid plaques in the brains of patients with Alzheimer's disease. Alternatively spliced transcripts encoding different isoforms have been identified for this gene. [provided by RefSeq, Feb 2016]

SNCA Gene-Disease associations (from GenCC):

autosomal dominant Parkinson disease 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Parkinson disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
autosomal dominant Parkinson disease 1
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
Lewy body dementia
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
hereditary late onset Parkinson disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
parkinsonian-pyramidal syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SNCA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNCA	NM_000345.4 link	c.307-32740A>G		intron_variant	Intron 4 of 5	ENST00000394991.8	NP_000336.1	P37840-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000394991.8 link	c.307-32740A>G		intron_variant	Intron 4 of 5	1	NM_000345.4	ENSP00000378442.4		P37840-1

Frequencies

GnomAD3 genomes

AF:

0.813

AC:

123662

AN:

152030

Hom.:

51135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.951

Gnomad AMI

AF:

0.652

Gnomad AMR

AF:

0.823

Gnomad ASJ

AF:

0.790

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.879

Gnomad FIN

AF:

0.754

Gnomad MID

AF:

0.858

Gnomad NFE

AF:

0.722

Gnomad OTH

AF:

0.794

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.813

AC:

123772

AN:

152148

Hom.:

51187

Cov.:

AF XY:

0.817

AC XY:

60732

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.951

AC:

39509

AN:

41544

American (AMR)

AF:

0.824

AC:

12586

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.790

AC:

2743

AN:

3472

East Asian (EAS)

AF:

0.999

AC:

5169

AN:

5174

South Asian (SAS)

AF:

0.877

AC:

4230

AN:

4824

European-Finnish (FIN)

AF:

0.754

AC:

7968

AN:

10574

Middle Eastern (MID)

AF:

0.854

AC:

251

AN:

294

European-Non Finnish (NFE)

AF:

0.722

AC:

49043

AN:

67966

Other (OTH)

AF:

0.795

AC:

1680

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1125

2251

3376

4502

5627

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

876

1752

2628

3504

4380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.776

Hom.:

5994

Bravo

AF:

0.822

Asia WGS

AF:

0.940

AC:

3265

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.13

(source)

DANN

Benign

0.45

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over