rs3775442

Variant names:

• chr4-89794080-C-T
• rs3775442
• NM_000345.4:c.306+28166G>A

Variant summary

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

The NM_000345.4(SNCA):​c.306+28166G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0702 in 151,942 control chromosomes in the GnomAD database, including 806 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 0.070 (806 hom., cov: 32)
• Consequence: SNCA NM_000345.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.230
• Publications: 9 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: 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hereditary late onset Parkinson disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• parkinsonian-pyramidal syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.344 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.306+28166G>A		intron	N/A	NP_000336.1	P37840-1
	SNCA	NM_001146054.2		c.306+28166G>A		intron	N/A	NP_001139526.1	P37840-1
	SNCA	NM_001146055.2		c.306+28166G>A		intron	N/A	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.306+28166G>A		intron	N/A	ENSP00000378442.4	P37840-1
	SNCA	ENST00000394986.5	TSL:1	c.306+28166G>A		intron	N/A	ENSP00000378437.1	P37840-1
	SNCA	ENST00000394989.6	TSL:1	c.264+28166G>A		intron	N/A	ENSP00000378440.2	P37840-3

Frequencies

GnomAD3 genomes AF: 0.0702 AC: 10660 AN: 151824 Hom.: 805 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0992

Gnomad ASJ AF: 0.0580

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0491

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0738

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

GnomAD4 genome AF: 0.0702 AC: 10666 AN: 151942 Hom.: 806 Cov.: 32 AF XY: 0.0737 AC XY: 5474 AN XY: 74230

African (AFR) AF: 0.119 AC: 4940 AN: 41400

American (AMR) AF: 0.0989 AC: 1510 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0580 AC: 201 AN: 3466

East Asian (EAS) AF: 0.358 AC: 1842 AN: 5148

South Asian (SAS) AF: 0.104 AC: 498 AN: 4804

European-Finnish (FIN) AF: 0.0491 AC: 518 AN: 10542

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0143 AC: 974 AN: 67998

Other (OTH) AF: 0.0768 AC: 162 AN: 2110

Alfa AF: 0.0385 Hom.: 1683

Bravo AF: 0.0798

Asia WGS AF: 0.236 AC: 818 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	5.6
DANN	Benign	0.62
PhyloP100		-0.23
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3775442;

hg19: chr4-90715231;