4-89836354-T-C

Variant names:

• chr4-89836354-T-C
• rs1372520
• NM_000345.4:c.-26+608A>G

Variant summary

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

The NM_000345.4(SNCA):​c.-26+608A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.775 in 152,666 control chromosomes in the GnomAD database, including 46,055 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 (45882 hom., cov: 32)
  • Exomes 𝑓: 0.80 (173 hom.)
• Consequence: SNCA NM_000345.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.336

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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.841 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNCA	NM_000345.4	c.-26+608A>G		intron_variant	Intron 1 of 5	ENST00000394991.8	NP_000336.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000394991.8	c.-26+608A>G		intron_variant	Intron 1 of 5	1	NM_000345.4	ENSP00000378442.4

Frequencies

GnomAD3 genomes AF: 0.775 AC: 117874 AN: 152032 Hom.: 45852 Cov.: 32

Gnomad AFR AF: 0.779

Gnomad AMI AF: 0.818

Gnomad AMR AF: 0.733

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.862

Gnomad SAS AF: 0.665

Gnomad FIN AF: 0.816

Gnomad MID AF: 0.710

Gnomad NFE AF: 0.781

Gnomad OTH AF: 0.766

GnomAD4 exome AF: 0.798 AC: 412 AN: 516 Hom.: 173 Cov.: 0 AF XY: 0.818 AC XY: 270 AN XY: 330

Gnomad4 AFR exome AF: 0.333

Gnomad4 AMR exome AF: 0.833

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.929

Gnomad4 SAS exome AF: 0.688

Gnomad4 FIN exome AF: 0.875

Gnomad4 NFE exome AF: 0.799

Gnomad4 OTH exome AF: 0.850

GnomAD4 genome AF: 0.775 AC: 117949 AN: 152150 Hom.: 45882 Cov.: 32 AF XY: 0.772 AC XY: 57482 AN XY: 74414

Gnomad4 AFR AF: 0.779

Gnomad4 AMR AF: 0.732

Gnomad4 ASJ AF: 0.706

Gnomad4 EAS AF: 0.862

Gnomad4 SAS AF: 0.665

Gnomad4 FIN AF: 0.816

Gnomad4 NFE AF: 0.781

Gnomad4 OTH AF: 0.763

Alfa AF: 0.775 Hom.: 5696

Bravo AF: 0.775

Asia WGS AF: 0.751 AC: 2613 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	12
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1372520; hg19: chr4-90757505;