rs3857053

Variant names:

• chr4-89724523-C-T
• rs3857053
• NM_000345.4:c.*2105G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000345.4(SNCA):​c.*2105G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 151,694 control chromosomes in the GnomAD database, including 7,218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (7218 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: SNCA NM_000345.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0930
• Publications: 15 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• 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

LOC124900602 (HGNC:):

ENSG00000251095 (HGNC:53614):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 4-89724523-C-T is Benign according to our data. Variant chr4-89724523-C-T is described in ClinVar as Benign. ClinVar VariationId is 350064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000345.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNCA	NM_000345.4	MANE Select	c.*2105G>A		3_prime_UTR	Exon 6 of 6	NP_000336.1	P37840-1
	SNCA	NM_001146054.2		c.*2105G>A		3_prime_UTR	Exon 6 of 6	NP_001139526.1	P37840-1
	SNCA	NM_001146055.2		c.*2105G>A		3_prime_UTR	Exon 6 of 6	NP_001139527.1	P37840-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNCA	ENST00000394991.8	TSL:1 MANE Select	c.*2105G>A		3_prime_UTR	Exon 6 of 6	ENSP00000378442.4	P37840-1
	SNCA	ENST00000394989.6	TSL:1	c.*2105G>A		3_prime_UTR	Exon 5 of 5	ENSP00000378440.2	P37840-3
	SNCA	ENST00000618500.4	TSL:1	c.*2105G>A		3_prime_UTR	Exon 5 of 5	ENSP00000484044.1	P37840-3

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35785 AN: 151578 Hom.: 7203 Cov.: 31

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.530

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.207

Gnomad NFE AF: 0.0700

Gnomad OTH AF: 0.224

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.236 AC: 35842 AN: 151694 Hom.: 7218 Cov.: 31 AF XY: 0.239 AC XY: 17753 AN XY: 74142

African (AFR) AF: 0.514 AC: 21194 AN: 41244

American (AMR) AF: 0.246 AC: 3753 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 433 AN: 3466

East Asian (EAS) AF: 0.529 AC: 2718 AN: 5138

South Asian (SAS) AF: 0.270 AC: 1296 AN: 4794

European-Finnish (FIN) AF: 0.103 AC: 1085 AN: 10562

Middle Eastern (MID) AF: 0.217 AC: 63 AN: 290

European-Non Finnish (NFE) AF: 0.0700 AC: 4758 AN: 67954

Other (OTH) AF: 0.227 AC: 477 AN: 2102

Alfa AF: 0.170 Hom.: 638

Bravo AF: 0.264

Asia WGS AF: 0.427 AC: 1481 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Parkinson Disease, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.6
DANN	Benign	0.27
PhyloP100		-0.093
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3857053; hg19: chr4-90645674; COSMIC: COSV105212776; COSMIC: COSV105212776;