rs3775422

Variant names:

• chr4-89733513-G-A
• rs3775422
• NM_000345.4:c.307-4236C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-89733513-G-A
• chr4-89733513-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000345.4(SNCA):​c.307-4236C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 151,906 control chromosomes in the GnomAD database, including 7,524 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 0.24 (7524 hom., cov: 32)
• Consequence: SNCA NM_000345.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.549
• Publications: 2 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: 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

ENSG00000251095 (HGNC:53614):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.519 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNCA	NM_000345.4	MANE Select	c.307-4236C>T		intron	N/A	NP_000336.1
	SNCA	NM_001146054.2		c.307-4236C>T		intron	N/A	NP_001139526.1
	SNCA	NM_001146055.2		c.307-4236C>T		intron	N/A	NP_001139527.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNCA	ENST00000394991.8	TSL:1 MANE Select	c.307-4236C>T		intron	N/A	ENSP00000378442.4
	SNCA	ENST00000394986.5	TSL:1	c.307-4236C>T		intron	N/A	ENSP00000378437.1
	SNCA	ENST00000394989.6	TSL:1	c.265-4236C>T		intron	N/A	ENSP00000378440.2

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36385 AN: 151786 Hom.: 7504 Cov.: 32

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.0700

Gnomad OTH AF: 0.225

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

GnomAD4 genome AF: 0.240 AC: 36449 AN: 151906 Hom.: 7524 Cov.: 32 AF XY: 0.243 AC XY: 18034 AN XY: 74252

African (AFR) AF: 0.525 AC: 21715 AN: 41396

American (AMR) AF: 0.248 AC: 3781 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 433 AN: 3472

East Asian (EAS) AF: 0.533 AC: 2758 AN: 5178

South Asian (SAS) AF: 0.272 AC: 1310 AN: 4816

European-Finnish (FIN) AF: 0.103 AC: 1088 AN: 10550

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.0700 AC: 4755 AN: 67930

Other (OTH) AF: 0.227 AC: 479 AN: 2106

Alfa AF: 0.172 Hom.: 651

Bravo AF: 0.267

Asia WGS AF: 0.427 AC: 1469 AN: 3450

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.49
DANN	Benign	0.32
PhyloP100		-0.55
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: rs3775422; hg19: chr4-90654664;