4-89713401-A-G

Variant names:

• chr4-89713401-A-G
• rs2572323
• ENST00000673902.1:c.391-11017T>C

Variant summary

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

The ENST00000673902.1(SNCA):​c.391-11017T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.749 in 151,564 control chromosomes in the GnomAD database, including 42,785 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 (42785 hom., cov: 32)
• Consequence: SNCA ENST00000673902.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.642
• Publications: 5 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124900602	XR_007058466.1	n.9902-6425A>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000673902.1	c.391-11017T>C		intron_variant	Intron 5 of 6			ENSP00000501102.1
ENSG00000251095	ENST00000507916.6	n.256-6425A>G		intron_variant	Intron 2 of 2	3
ENSG00000251095	ENST00000508021.5	n.448-12983A>G		intron_variant	Intron 4 of 4	4

Frequencies

GnomAD3 genomes AF: 0.749 AC: 113372 AN: 151444 Hom.: 42752 Cov.: 32

Gnomad AFR AF: 0.780

Gnomad AMI AF: 0.663

Gnomad AMR AF: 0.788

Gnomad ASJ AF: 0.712

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.851

Gnomad FIN AF: 0.736

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.727

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

GnomAD4 genome AF: 0.749 AC: 113463 AN: 151564 Hom.: 42785 Cov.: 32 AF XY: 0.753 AC XY: 55782 AN XY: 74042

African (AFR) AF: 0.780 AC: 32208 AN: 41312

American (AMR) AF: 0.788 AC: 12026 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.712 AC: 2459 AN: 3456

East Asian (EAS) AF: 0.998 AC: 5153 AN: 5162

South Asian (SAS) AF: 0.848 AC: 4079 AN: 4808

European-Finnish (FIN) AF: 0.736 AC: 7702 AN: 10462

Middle Eastern (MID) AF: 0.760 AC: 222 AN: 292

European-Non Finnish (NFE) AF: 0.700 AC: 47476 AN: 67804

Other (OTH) AF: 0.730 AC: 1541 AN: 2112

Alfa AF: 0.713 Hom.: 4848

Bravo AF: 0.753

Asia WGS AF: 0.911 AC: 3164 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.56
DANN	Benign	0.64
PhyloP100		-0.64

Splicing

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

Other links and lift over

dbSNP: rs2572323; hg19: chr4-90634552;