rs17016074

Positions:

• chr4-89726127-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.25

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]

LOC124900602 (HGNC:):

ACMG classification

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	UniProt
SNCA	NM_000345.4	c.*501C>T		3_prime_UTR_variant	6/6	ENST00000394991.8
LOC124900602	XR_007058466.1	n.16004G>A		non_coding_transcript_exon_variant	3/3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0447 AC: 6788 AN: 151852 Hom.: 420 Cov.: 32

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: 3 AN: 854 Hom.: 0 Cov.: 0 AF XY: 0.00591 AC XY: 3 AN XY: 508

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.: 32 AF XY: 0.0436 AC XY: 3236 AN XY: 74256

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.: 34

Bravo AF: 0.0509

Asia WGS AF: 0.0170 AC: 59 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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	13
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

Other links and lift over

dbSNP: rs17016074; hg19: chr4-90647278;