rs356221

Variant names:

• chr4-89721313-A-T
• rs356221
• XR_007058466.1:n.11190A>T

Variant summary

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

The XR_007058466.1(LOC124900602):​n.11190A>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 151,926 control chromosomes in the GnomAD database, including 16,270 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 0.44 (16270 hom., cov: 31)
• Consequence: LOC124900602 XR_007058466.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45
• Publications: 19 publications found

Genes affected

LOC124900602 (HGNC:):

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.542 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124900602	XR_007058466.1	n.11190A>T		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000673902.1	c.390+7881T>A		intron_variant	Intron 5 of 6			ENSP00000501102.1
ENSG00000251095	ENST00000508021.5	n.448-5071A>T		intron_variant	Intron 4 of 4	4
ENSG00000251095	ENST00000621944.1	n.91+881A>T		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.442 AC: 67141 AN: 151808 Hom.: 16272 Cov.: 31

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.528

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.546

Gnomad OTH AF: 0.448

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

GnomAD4 genome AF: 0.442 AC: 67148 AN: 151926 Hom.: 16270 Cov.: 31 AF XY: 0.443 AC XY: 32860 AN XY: 74236

African (AFR) AF: 0.224 AC: 9281 AN: 41450

American (AMR) AF: 0.489 AC: 7465 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1722 AN: 3468

East Asian (EAS) AF: 0.401 AC: 2068 AN: 5156

South Asian (SAS) AF: 0.493 AC: 2368 AN: 4806

European-Finnish (FIN) AF: 0.528 AC: 5570 AN: 10556

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.546 AC: 37105 AN: 67920

Other (OTH) AF: 0.442 AC: 934 AN: 2112

Alfa AF: 0.478 Hom.: 2292

Bravo AF: 0.426

Asia WGS AF: 0.397 AC: 1381 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.70
DANN	Benign	0.55
PhyloP100		-1.5

Splicing

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

Other links and lift over

dbSNP: rs356221; hg19: chr4-90642464;