rs10024743

Variant names:

• chr4-89726489-A-C
• rs10024743
• NM_000345.4:c.*139T>G

Your query was ambiguous. Multiple possible variants found:

• chr4-89726489-A-C
• chr4-89726489-A-G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 12 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• 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:53614):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000345.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNCA	NM_000345.4	MANE Select	c.*139T>G		3_prime_UTR	Exon 6 of 6	NP_000336.1	P37840-1
	SNCA	NM_001146054.2		c.*139T>G		3_prime_UTR	Exon 6 of 6	NP_001139526.1	P37840-1
	SNCA	NM_001146055.2		c.*139T>G		3_prime_UTR	Exon 6 of 6	NP_001139527.1	P37840-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNCA	ENST00000394991.8	TSL:1 MANE Select	c.*139T>G		3_prime_UTR	Exon 6 of 6	ENSP00000378442.4	P37840-1
	SNCA	ENST00000394986.5	TSL:1	c.*139T>G		3_prime_UTR	Exon 6 of 6	ENSP00000378437.1	P37840-1
	SNCA	ENST00000394989.6	TSL:1	c.*139T>G		3_prime_UTR	Exon 5 of 5	ENSP00000378440.2	P37840-3

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

African (AFR) AF: 0.0195 AC: 339 AN: 17408

American (AMR) AF: 0.00179 AC: 73 AN: 40740

Ashkenazi Jewish (ASJ) AF: 0.00392 AC: 80 AN: 20424

East Asian (EAS) AF: 0.0000570 AC: 2 AN: 35104

South Asian (SAS) AF: 0.0000447 AC: 3 AN: 67112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45364

Middle Eastern (MID) AF: 0.000727 AC: 3 AN: 4126

European-Non Finnish (NFE) AF: 0.000195 AC: 70 AN: 358544

Other (OTH) AF: 0.00259 AC: 85 AN: 32790

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

African (AFR) AF: 0.0200 AC: 833 AN: 41572

American (AMR) AF: 0.00752 AC: 115 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68040

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00404 Hom.: 1

Bravo AF: 0.00748

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Lewy body dementia;C1854182:Autosomal dominant Parkinson disease 4;C1868595:Autosomal dominant Parkinson disease 1 (1)
-	-	1	not provided (1)
-	-	1	Parkinson Disease, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs10024743; hg19: chr4-90647640;