4-89713869-T-C

Variant names:

• chr4-89713869-T-C
• rs181489
• ENST00000673902.1:c.391-11485A>G

Variant summary

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

The ENST00000673902.1(SNCA):​c.391-11485A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.75 in 152,102 control chromosomes in the GnomAD database, including 43,122 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 0.75 (43122 hom., cov: 33)
• Consequence: SNCA ENST00000673902.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.483
• Publications: 20 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 Gene-Disease associations (from GenCC):

• autosomal dominant Parkinson disease 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• autosomal dominant Parkinson disease 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Lewy body dementia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hereditary late onset Parkinson disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• parkinsonian-pyramidal syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000251095 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• 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 rank	MANE	Protein	UniProt
LOC124900602	XR_007058466.1	n.9902-5957T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000673902.1	c.391-11485A>G		intron_variant	Intron 5 of 6			ENSP00000501102.1
ENSG00000251095	ENST00000507916.6	n.256-5957T>C		intron_variant	Intron 2 of 2	3
ENSG00000251095	ENST00000508021.5	n.448-12515T>C		intron_variant	Intron 4 of 4	4

Frequencies

GnomAD3 genomes AF: 0.750 AC: 113996 AN: 151984 Hom.: 43090 Cov.: 33

Gnomad AFR AF: 0.781

Gnomad AMI AF: 0.663

Gnomad AMR AF: 0.789

Gnomad ASJ AF: 0.713

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.850

Gnomad FIN AF: 0.739

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.702

Gnomad OTH AF: 0.727

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

GnomAD4 genome AF: 0.750 AC: 114085 AN: 152102 Hom.: 43122 Cov.: 33 AF XY: 0.755 AC XY: 56110 AN XY: 74346

African (AFR) AF: 0.781 AC: 32393 AN: 41496

American (AMR) AF: 0.790 AC: 12062 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.713 AC: 2476 AN: 3472

East Asian (EAS) AF: 0.998 AC: 5173 AN: 5182

South Asian (SAS) AF: 0.848 AC: 4091 AN: 4824

European-Finnish (FIN) AF: 0.739 AC: 7824 AN: 10582

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.702 AC: 47701 AN: 67958

Other (OTH) AF: 0.729 AC: 1538 AN: 2110

Alfa AF: 0.710 Hom.: 4559

Bravo AF: 0.753

Asia WGS AF: 0.910 AC: 3162 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.8
DANN	Benign	0.72
PhyloP100		-0.48

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs181489; hg19: chr4-90635020;