NM_000345.4:c.163+1543G>A

Variant names:

• chr4-89826600-C-T
• rs1811442
• NM_000345.4:c.163+1543G>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.163+1543G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.78 in 151,832 control chromosomes in the GnomAD database, including 46,351 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 0.78 (46351 hom., cov: 29)
• Consequence: SNCA NM_000345.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.372
• Publications: 6 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.832 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.163+1543G>A		intron	N/A	NP_000336.1
	SNCA	NM_001146054.2		c.163+1543G>A		intron	N/A	NP_001139526.1
	SNCA	NM_001146055.2		c.163+1543G>A		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.163+1543G>A		intron	N/A	ENSP00000378442.4
	SNCA	ENST00000394986.5	TSL:1	c.163+1543G>A		intron	N/A	ENSP00000378437.1
	SNCA	ENST00000394989.6	TSL:1	c.122-4212G>A		intron	N/A	ENSP00000378440.2

Frequencies

GnomAD3 genomes AF: 0.780 AC: 118373 AN: 151714 Hom.: 46316 Cov.: 29

Gnomad AFR AF: 0.781

Gnomad AMI AF: 0.819

Gnomad AMR AF: 0.733

Gnomad ASJ AF: 0.716

Gnomad EAS AF: 0.853

Gnomad SAS AF: 0.685

Gnomad FIN AF: 0.813

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.774

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

GnomAD4 genome AF: 0.780 AC: 118453 AN: 151832 Hom.: 46351 Cov.: 29 AF XY: 0.777 AC XY: 57658 AN XY: 74196

African (AFR) AF: 0.781 AC: 32348 AN: 41396

American (AMR) AF: 0.733 AC: 11174 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.716 AC: 2482 AN: 3466

East Asian (EAS) AF: 0.853 AC: 4403 AN: 5162

South Asian (SAS) AF: 0.685 AC: 3295 AN: 4808

European-Finnish (FIN) AF: 0.813 AC: 8572 AN: 10540

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.789 AC: 53589 AN: 67902

Other (OTH) AF: 0.771 AC: 1628 AN: 2112

Alfa AF: 0.780 Hom.: 7837

Bravo AF: 0.780

Asia WGS AF: 0.757 AC: 2631 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	12
DANN	Benign	0.77
PhyloP100		-0.37
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: rs1811442; hg19: chr4-90747751;