rs17016074

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000345.4(SNCA):c.*501C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0445 in 152,826 control chromosomes in the GnomAD database, including 422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 422 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 0 hom. )

Consequence

SNCA
NM_000345.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.25

Publications

18 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:

LOC124900602 (HGNC:):

LOC124900602 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 4-89726127-G-A is Benign according to our data. Variant chr4-89726127-G-A is described in ClinVar as Benign. ClinVar VariationId is 350098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNCA	NM_000345.4 link	c.*501C>T		3_prime_UTR_variant	Exon 6 of 6	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.*501C>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_000345.4	ENSP00000378442.4		P37840-1

Frequencies

GnomAD3 genomes

AF:

0.0447

AC:

6788

AN:

151852

Hom.:

420

Cov.:

show subpopulations

Gnomad AFR

AF:

0.138

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0233

Gnomad ASJ

AF:

0.0297

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00997

Gnomad FIN

AF:

0.000758

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.00660

Gnomad OTH

AF:

0.0460

GnomAD4 exome

AF:

0.00351

AC:

AN:

854

Hom.:

Cov.:

AF XY:

0.00591

AC XY:

AN XY:

508

show subpopulations

African (AFR)

AF:

0.250

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

428

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00641

AC:

AN:

312

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

AF:

0.0448

AC:

6805

AN:

151972

Hom.:

422

Cov.:

AF XY:

0.0436

AC XY:

3236

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.138

AC:

5706

AN:

41412

American (AMR)

AF:

0.0233

AC:

355

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.0297

AC:

103

AN:

3464

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0102

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.000758

AC:

AN:

10552

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00662

AC:

450

AN:

67980

Other (OTH)

AF:

0.0455

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

306

611

917

1222

1528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0326

Hom.:

Bravo

AF:

0.0509

Asia WGS

AF:

0.0170

AC:

AN:

3470

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lewy body dementia;C1868595:Autosomal dominant Parkinson disease 1

Benign:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Parkinson Disease, Dominant

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.83

PhyloP100

3.3

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over