4-89836689-T-C

Position:

• chr4-89836689-T-C

Variant summary

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

The NM_000345.4(SNCA):​c.-26+273A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.793 in 152,164 control chromosomes in the GnomAD database, including 47,974 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 0.79 (47902 hom., cov: 30)
  • Exomes 𝑓: 0.77 (72 hom.)
• Consequence: SNCA NM_000345.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.205

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-AS1 (HGNC:50600): (SNCA antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNCA	NM_000345.4	c.-26+273A>G		intron_variant		ENST00000394991.8
SNCA-AS1	NR_045481.1	n.289T>C		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNCA	ENST00000394991.8	c.-26+273A>G		intron_variant		1	NM_000345.4	P1
SNCA-AS1	ENST00000513653.1	n.282T>C		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes AF: 0.793 AC: 120370 AN: 151824 Hom.: 47855 Cov.: 30

Gnomad AFR AF: 0.812

Gnomad AMI AF: 0.820

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.717

Gnomad EAS AF: 0.855

Gnomad SAS AF: 0.677

Gnomad FIN AF: 0.831

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.794

Gnomad OTH AF: 0.784

GnomAD4 exome AF: 0.775 AC: 172 AN: 222 Hom.: 72 Cov.: 0 AF XY: 0.753 AC XY: 128 AN XY: 170

Gnomad4 AFR exome AF: 1.00

Gnomad4 AMR exome AF: 1.00

Gnomad4 ASJ exome AF: 0.333

Gnomad4 EAS exome AF: 0.833

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.667

Gnomad4 NFE exome AF: 0.787

Gnomad4 OTH exome AF: 0.714

GnomAD4 genome AF: 0.793 AC: 120466 AN: 151942 Hom.: 47902 Cov.: 30 AF XY: 0.791 AC XY: 58712 AN XY: 74254

Gnomad4 AFR AF: 0.813

Gnomad4 AMR AF: 0.742

Gnomad4 ASJ AF: 0.717

Gnomad4 EAS AF: 0.855

Gnomad4 SAS AF: 0.676

Gnomad4 FIN AF: 0.831

Gnomad4 NFE AF: 0.794

Gnomad4 OTH AF: 0.781

Alfa AF: 0.792 Hom.: 10416

Bravo AF: 0.794

Asia WGS AF: 0.758 AC: 2637 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.8
DANN	Benign	0.61

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: rs2245801; hg19: chr4-90757840;