rs3756059

Positions:

• chr4-89836121-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001375288.1(SNCA):​c.-26+6C>T variant causes a splice region, 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. 2/3 splice prediction tools predict no significant impact on normal splicing. 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_001375288.1 splice_region, intron
• Scores: Splicing: ADA: 0.00004088
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.312

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
SNCA	NM_000345.4	c.-25-429C>T		intron_variant		ENST00000394991.8	NP_000336.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000394991.8	c.-25-429C>T		intron_variant		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

Gnomad4 AFR exome AF: 0.694

Gnomad4 AMR exome AF: 0.575

Gnomad4 ASJ exome AF: 0.492

Gnomad4 EAS exome AF: 0.865

Gnomad4 SAS exome AF: 0.511

Gnomad4 FIN exome AF: 0.556

Gnomad4 NFE exome AF: 0.496

Gnomad4 OTH exome AF: 0.515

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

Gnomad4 AFR AF: 0.704

Gnomad4 AMR AF: 0.554

Gnomad4 ASJ AF: 0.499

Gnomad4 EAS AF: 0.860

Gnomad4 SAS AF: 0.540

Gnomad4 FIN AF: 0.572

Gnomad4 NFE AF: 0.510

Gnomad4 OTH AF: 0.556

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs3756059; hg19: chr4-90757272;