rs9864

Variant names:

• chr10-86962641-A-T
• rs9864
• NM_003087.3:c.329A>T

Variant summary

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

The NM_003087.3(SNCG):​c.329A>T​(p.Glu110Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,610,028 control chromosomes in the GnomAD database, including 46,434 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.22 (3812 hom., cov: 32)
  • Exomes 𝑓: 0.24 (42622 hom.)
• Consequence: SNCG NM_003087.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.880
• Publications: 34 publications found

Genes affected

SNCG (HGNC:11141): (synuclein gamma) This gene encodes a member of the synuclein family of proteins which are believed to be involved in the pathogenesis of neurodegenerative diseases. Mutations in this gene have also been associated with breast tumor development. [provided by RefSeq, Jan 2010]

MMRN2 (HGNC:19888): (multimerin 2) This gene encodes a protein belonging to the member of elastin microfibril interface-located (EMILIN) protein family. This family member is an extracellular matrix glycoprotein that can interfere with tumor angiogenesis and growth. It serves as a transforming growth factor beta antagonist and can interfere with the VEGF-A/VEGFR2 pathway. A related pseudogene has been identified on chromosome 6. [provided by RefSeq, Aug 2012]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045140684).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNCG	NM_003087.3	c.329A>T	p.Glu110Val	missense_variant	Exon 4 of 5	ENST00000372017.4	NP_003078.2
SNCG	NM_001330120.2	c.381A>T	p.Ter127Cysext*?	stop_lost	Exon 6 of 7		NP_001317049.1
SNCG	XM_047425681.1	c.656A>T	p.Glu219Val	missense_variant	Exon 6 of 7		XP_047281637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNCG	ENST00000372017.4	c.329A>T	p.Glu110Val	missense_variant	Exon 4 of 5	1	NM_003087.3	ENSP00000361087.3

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33344 AN: 151822 Hom.: 3815 Cov.: 32

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.0720

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.224

GnomAD2 exomes AF: 0.221 AC: 54619 AN: 247426 AF XY: 0.227

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.223

Gnomad EAS exome AF: 0.0756

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.241

Gnomad OTH exome AF: 0.233

GnomAD4 exome AF: 0.238 AC: 347188 AN: 1458088 Hom.: 42622 Cov.: 32 AF XY: 0.240 AC XY: 174088 AN XY: 725308

African (AFR) AF: 0.181 AC: 6061 AN: 33444

American (AMR) AF: 0.193 AC: 8575 AN: 44476

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 5924 AN: 26048

East Asian (EAS) AF: 0.0769 AC: 3050 AN: 39682

South Asian (SAS) AF: 0.297 AC: 25480 AN: 85798

European-Finnish (FIN) AF: 0.198 AC: 10538 AN: 53186

Middle Eastern (MID) AF: 0.208 AC: 1194 AN: 5752

European-Non Finnish (NFE) AF: 0.245 AC: 272277 AN: 1109436

Other (OTH) AF: 0.234 AC: 14089 AN: 60266

GnomAD4 genome AF: 0.219 AC: 33338 AN: 151940 Hom.: 3812 Cov.: 32 AF XY: 0.217 AC XY: 16138 AN XY: 74250

African (AFR) AF: 0.191 AC: 7928 AN: 41426

American (AMR) AF: 0.213 AC: 3250 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 798 AN: 3468

East Asian (EAS) AF: 0.0726 AC: 374 AN: 5152

South Asian (SAS) AF: 0.311 AC: 1492 AN: 4798

European-Finnish (FIN) AF: 0.191 AC: 2024 AN: 10604

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.247 AC: 16751 AN: 67890

Other (OTH) AF: 0.222 AC: 469 AN: 2112

Alfa AF: 0.235 Hom.: 1414

Bravo AF: 0.215

TwinsUK AF: 0.268 AC: 993

ALSPAC AF: 0.257 AC: 989

ESP6500AA AF: 0.187 AC: 824

ESP6500EA AF: 0.249 AC: 2144

ExAC AF: 0.225 AC: 27250

Asia WGS AF: 0.227 AC: 789 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.88
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.056
Sift	Benign	0.14	T
Sift4G	Benign	0.23	T
Polyphen		0.17	B
Vest4		0.17
MPC		0.15
ClinPred		0.0085	T
GERP RS		2.6
Varity_R		0.080
gMVP		0.35
Mutation Taster		=125/75	polymorphism (auto)

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: rs9864; hg19: chr10-88722398; COSMIC: COSV62317993; COSMIC: COSV62317993;