rs3756059

Variant names:

• chr4-89836121-G-A
• rs3756059
• NM_000345.4:c.-25-429C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-89836121-G-A
• chr4-89836121-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.-25-429C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 243,138 control chromosomes in the GnomAD database, including 40,276 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 0.58 (26806 hom., cov: 31)
  • Exomes 𝑓: 0.53 (13470 hom.)
• Consequence: SNCA NM_000345.4 intron
• Scores: Splicing: ADA: 0.00004088
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.312
• 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: 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 = 0.838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNCA	NM_000345.4	c.-25-429C>T		intron_variant	Intron 1 of 5	ENST00000394991.8	NP_000336.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000394991.8	c.-25-429C>T		intron_variant	Intron 1 of 5	1	NM_000345.4	ENSP00000378442.4

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88711 AN: 151688 Hom.: 26785 Cov.: 31

Gnomad AFR AF: 0.704

Gnomad AMI AF: 0.469

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.860

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.510

Gnomad OTH AF: 0.558

GnomAD4 exome AF: 0.529 AC: 48276 AN: 91332 Hom.: 13470 Cov.: 0 AF XY: 0.526 AC XY: 25602 AN XY: 48632

African (AFR) AF: 0.694 AC: 1791 AN: 2582

American (AMR) AF: 0.575 AC: 2357 AN: 4102

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 1110 AN: 2258

East Asian (EAS) AF: 0.865 AC: 3866 AN: 4468

South Asian (SAS) AF: 0.511 AC: 7035 AN: 13776

European-Finnish (FIN) AF: 0.556 AC: 2164 AN: 3892

Middle Eastern (MID) AF: 0.497 AC: 169 AN: 340

European-Non Finnish (NFE) AF: 0.496 AC: 27363 AN: 55212

Other (OTH) AF: 0.515 AC: 2421 AN: 4702

GnomAD4 genome AF: 0.585 AC: 88773 AN: 151806 Hom.: 26806 Cov.: 31 AF XY: 0.585 AC XY: 43389 AN XY: 74174

African (AFR) AF: 0.704 AC: 29148 AN: 41388

American (AMR) AF: 0.554 AC: 8466 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 1730 AN: 3464

East Asian (EAS) AF: 0.860 AC: 4394 AN: 5112

South Asian (SAS) AF: 0.540 AC: 2594 AN: 4800

European-Finnish (FIN) AF: 0.572 AC: 6030 AN: 10534

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.510 AC: 34644 AN: 67916

Other (OTH) AF: 0.556 AC: 1172 AN: 2108

Alfa AF: 0.541 Hom.: 7126

Bravo AF: 0.593

Asia WGS AF: 0.692 AC: 2402 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.7
DANN	Benign	0.62
PhyloP100		-0.31
PromoterAI		0.047	Neutral
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000041
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3756059; hg19: chr4-90757272;