4-89782082-A-G

Position:

• chr4-89782082-A-G

Variant summary

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

The NM_000345.4(SNCA):​c.306+40164T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.797 in 151,956 control chromosomes in the GnomAD database, including 48,849 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 0.80 (48849 hom., cov: 32)
• Consequence: SNCA NM_000345.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.388

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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNCA	NM_000345.4	c.306+40164T>C		intron_variant		ENST00000394991.8	NP_000336.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000394991.8	c.306+40164T>C		intron_variant		1	NM_000345.4	ENSP00000378442.4

Frequencies

GnomAD3 genomes AF: 0.797 AC: 121054 AN: 151836 Hom.: 48799 Cov.: 32

Gnomad AFR AF: 0.896

Gnomad AMI AF: 0.652

Gnomad AMR AF: 0.815

Gnomad ASJ AF: 0.793

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.878

Gnomad FIN AF: 0.754

Gnomad MID AF: 0.857

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.781

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

GnomAD4 genome AF: 0.797 AC: 121162 AN: 151956 Hom.: 48849 Cov.: 32 AF XY: 0.802 AC XY: 59537 AN XY: 74252

Gnomad4 AFR AF: 0.896

Gnomad4 AMR AF: 0.816

Gnomad4 ASJ AF: 0.793

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.876

Gnomad4 FIN AF: 0.754

Gnomad4 NFE AF: 0.721

Gnomad4 OTH AF: 0.783

Alfa AF: 0.747 Hom.: 8651

Bravo AF: 0.803

Asia WGS AF: 0.937 AC: 3253 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.0
DANN	Benign	0.64

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: rs356184; hg19: chr4-90703233;