rs748849

chr4-89813810-G-Achr4-89813810-G-C

Variant summary

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

The NM_000345.4(SNCA):c.306+8436C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.781 in 152,082 control chromosomes in the GnomAD database, including 46,542 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 (46542 hom., cov: 31)
• Consequence: SNCA NM_000345.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.210

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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.832 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNCA	NM_000345.4	c.306+8436C>T		intron_variant		ENST00000394991.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNCA	ENST00000394991.8	c.306+8436C>T		intron_variant		1	NM_000345.4	P1

Frequencies

GnomAD3 genomes AF: 0.781 AC: 118706 AN: 151964 Hom.: 46507 Cov.: 31

Gnomad AFR AF: 0.782

Gnomad AMI AF: 0.818

Gnomad AMR AF: 0.735

Gnomad ASJ AF: 0.715

Gnomad EAS AF: 0.853

Gnomad SAS AF: 0.686

Gnomad FIN AF: 0.813

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.791

Gnomad OTH AF: 0.776

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

GnomAD4 genome AF: 0.781 AC: 118786 AN: 152082 Hom.: 46542 Cov.: 31 AF XY: 0.778 AC XY: 57827 AN XY: 74350

Gnomad4 AFR AF: 0.782

Gnomad4 AMR AF: 0.734

Gnomad4 ASJ AF: 0.715

Gnomad4 EAS AF: 0.853

Gnomad4 SAS AF: 0.686

Gnomad4 FIN AF: 0.813

Gnomad4 NFE AF: 0.791

Gnomad4 OTH AF: 0.772

Alfa AF: 0.729 Hom.: 2229

Bravo AF: 0.781

Asia WGS AF: 0.758 AC: 2636 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	0.64
Dann	Benign	0.18

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: rs748849; hg19: chr4-90734961;