Variant chr4-89726127-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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

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 links:

LOC124900602 (HGNC:):

LOC124900602 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
SNCA	NM_000345.4 linkuse as main transcript	c.*501C>T		3_prime_UTR_variant	6/6	ENST00000394991.8	NP_000336.1
LOC124900602	XR_007058466.1 linkuse as main transcript	n.16004G>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000394991.8 linkuse as main transcript	c.*501C>T		3_prime_UTR_variant	6/6	1	NM_000345.4	ENSP00000378442	P1	P37840-1
	ENST00000659878.1 linkuse as main transcript	n.480-257G>A		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR exome

AF:

0.250

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:

0.00641

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0448

AC:

6805

AN:

151972

Hom.:

422

Cov.:

AF XY:

0.0436

AC XY:

3236

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.138

Gnomad4 AMR

AF:

0.0233

Gnomad4 ASJ

AF:

0.0297

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0102

Gnomad4 FIN

AF:

0.000758

Gnomad4 NFE

AF:

0.00662

Gnomad4 OTH

AF:

0.0455

Alfa

AF:

0.0291

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2022

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Parkinson Disease, Dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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

DANN

Benign

0.83

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