4-89726489-A-C

Position:

• chr4-89726489-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000345.4(SNCA):​c.*139T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 773,914 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (7 hom.)
• Consequence: SNCA NM_000345.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.25

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]

ENSG00000251095 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 4-89726489-A-C is Benign according to our data. Variant chr4-89726489-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 350103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00648 (987/152302) while in subpopulation AFR AF= 0.02 (833/41572). AF 95% confidence interval is 0.0189. There are 6 homozygotes in gnomad4. There are 523 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 987 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNCA	NM_000345.4	c.*139T>G		3_prime_UTR_variant	6/6	ENST00000394991.8	NP_000336.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000394991.8	c.*139T>G		3_prime_UTR_variant	6/6	1	NM_000345.4	ENSP00000378442.4

Frequencies

GnomAD3 genomes AF: 0.00645 AC: 982 AN: 152184 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00574

GnomAD4 exome AF: 0.00105 AC: 655 AN: 621612 Hom.: 7 Cov.: 7 AF XY: 0.000814 AC XY: 274 AN XY: 336686

Gnomad4 AFR exome AF: 0.0195

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00392

Gnomad4 EAS exome AF: 0.0000570

Gnomad4 SAS exome AF: 0.0000447

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000195

Gnomad4 OTH exome AF: 0.00259

GnomAD4 genome AF: 0.00648 AC: 987 AN: 152302 Hom.: 6 Cov.: 32 AF XY: 0.00702 AC XY: 523 AN XY: 74466

Gnomad4 AFR AF: 0.0200

Gnomad4 AMR AF: 0.00752

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00415 Hom.: 1

Bravo AF: 0.00748

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

Parkinson Disease, Dominant Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Lewy body dementia;C1854182:Autosomal dominant Parkinson disease 4;C1868595:Autosomal dominant Parkinson disease 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.82

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: rs10024743; hg19: chr4-90647640;