4-89836158-A-G

Variant names:

• chr4-89836158-A-G
• rs1372519
• ENST00000618500.4:c.-57T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000618500.4(SNCA):​c.-57T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 209,584 control chromosomes in the GnomAD database, including 62,143 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 0.77 (45322 hom., cov: 29)
  • Exomes 𝑓: 0.76 (16821 hom.)
• Consequence: SNCA ENST00000618500.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.877
• Publications: 14 publications found

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

Our verdict: Benign. The variant received -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 = 0.841 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNCA	NM_000345.4	c.-25-466T>C		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.-25-466T>C		intron_variant	Intron 1 of 5	1	NM_000345.4	ENSP00000378442.4

Frequencies

GnomAD3 genomes AF: 0.772 AC: 116960 AN: 151476 Hom.: 45294 Cov.: 29

Gnomad AFR AF: 0.769

Gnomad AMI AF: 0.820

Gnomad AMR AF: 0.730

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.862

Gnomad SAS AF: 0.666

Gnomad FIN AF: 0.815

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.781

Gnomad OTH AF: 0.766

GnomAD4 exome AF: 0.757 AC: 43897 AN: 57990 Hom.: 16821 Cov.: 0 AF XY: 0.749 AC XY: 22912 AN XY: 30574

African (AFR) AF: 0.753 AC: 1202 AN: 1596

American (AMR) AF: 0.750 AC: 2738 AN: 3650

Ashkenazi Jewish (ASJ) AF: 0.691 AC: 925 AN: 1338

East Asian (EAS) AF: 0.865 AC: 2849 AN: 3294

South Asian (SAS) AF: 0.652 AC: 5121 AN: 7852

European-Finnish (FIN) AF: 0.793 AC: 1790 AN: 2258

Middle Eastern (MID) AF: 0.716 AC: 146 AN: 204

European-Non Finnish (NFE) AF: 0.772 AC: 26914 AN: 34850

Other (OTH) AF: 0.750 AC: 2212 AN: 2948

GnomAD4 genome AF: 0.772 AC: 117032 AN: 151594 Hom.: 45322 Cov.: 29 AF XY: 0.769 AC XY: 56957 AN XY: 74034

African (AFR) AF: 0.769 AC: 31763 AN: 41298

American (AMR) AF: 0.729 AC: 11117 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2446 AN: 3466

East Asian (EAS) AF: 0.862 AC: 4392 AN: 5096

South Asian (SAS) AF: 0.665 AC: 3183 AN: 4784

European-Finnish (FIN) AF: 0.815 AC: 8566 AN: 10510

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.781 AC: 53001 AN: 67888

Other (OTH) AF: 0.762 AC: 1607 AN: 2108

Alfa AF: 0.774 Hom.: 9685

Bravo AF: 0.772

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.2
DANN	Benign	0.65
PhyloP100		-0.88
PromoterAI		-0.090	Neutral
Mutation Taster		=299/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1372519; hg19: chr4-90757309;