4-89724308-T-A

Position:

• chr4-89724308-T-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000345.4(SNCA):​c.*2320A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 152,036 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SNCA NM_000345.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.420

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]

LOC124900602 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 4-89724308-T-A is Benign according to our data. Variant chr4-89724308-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 904876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 253 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNCA	NM_000345.4	c.*2320A>T		3_prime_UTR_variant	6/6	ENST00000394991.8
LOC124900602	XR_007058466.1	n.14185T>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNCA	ENST00000394991.8	c.*2320A>T		3_prime_UTR_variant	6/6	1	NM_000345.4	P1
	ENST00000659878.1	n.480-2076T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 252 AN: 151918 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00576

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.00166 AC: 253 AN: 152036 Hom.: 2 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74292

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.0242

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.000284

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.00570

Alfa AF: 0.00196 Hom.: 1

Bravo AF: 0.00177

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Parkinson Disease, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.6
DANN	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs529553259; hg19: chr4-90645459;