rs4031753

Positions:

• chr4-89779010-C-G
• chr4-89779010-C-T

Variant summary

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

The NM_000345.4(SNCA):​c.306+43236G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 151,800 control chromosomes in the GnomAD database, including 6,112 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 0.22 (6112 hom., cov: 32)
• Consequence: SNCA NM_000345.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.754

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNCA	NM_000345.4	c.306+43236G>C		intron_variant		ENST00000394991.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNCA	ENST00000394991.8	c.306+43236G>C		intron_variant		1	NM_000345.4	P1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33319 AN: 151682 Hom.: 6092 Cov.: 32

Gnomad AFR AF: 0.455

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.207

Gnomad NFE AF: 0.0689

Gnomad OTH AF: 0.214

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

GnomAD4 genome AF: 0.220 AC: 33381 AN: 151800 Hom.: 6112 Cov.: 32 AF XY: 0.223 AC XY: 16555 AN XY: 74200

Gnomad4 AFR AF: 0.455

Gnomad4 AMR AF: 0.240

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.548

Gnomad4 SAS AF: 0.270

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.0689

Gnomad4 OTH AF: 0.217

Alfa AF: 0.134 Hom.: 383

Bravo AF: 0.245

Asia WGS AF: 0.434 AC: 1505 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.87
DANN	Benign	0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs4031753; hg19: chr4-90700161;