rs1472050

Positions:

• chr10-104735013-A-C
• chr10-104735013-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014978.3(SORCS3):​c.627+93059A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 152,172 control chromosomes in the GnomAD database, including 4,246 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 0.23 (4246 hom., cov: 32)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05

Genes affected

SORCS3 (HGNC:16699): (sortilin related VPS10 domain containing receptor 3) This gene encodes a type-I receptor transmembrane protein that is a member of the vacuolar protein sorting 10 receptor family. Proteins of this family are defined by a vacuolar protein sorting 10 domain at the N-terminus. The N-terminal segment of this domain has a consensus motif for proprotein convertase processing, and the C-terminal segment of this domain is characterized by ten conserved cysteine residues. The vacuolar protein sorting 10 domain is followed by a leucine-rich segment, a transmembrane domain, and a short C-terminal cytoplasmic domain that interacts with adaptor molecules. The transcript is expressed at high levels in the brain, and candidate gene studies suggest that genetic variation in this gene is associated with Alzheimer's disease. Consistent with this observation, knockdown of the gene in cell culture results in an increase in amyloid precursor protein processing. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORCS3	NM_014978.3	c.627+93059A>C		intron_variant		ENST00000369701.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORCS3	ENST00000369701.8	c.627+93059A>C		intron_variant		1	NM_014978.3	P1

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35122 AN: 152054 Hom.: 4232 Cov.: 32

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.226

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

GnomAD4 genome AF: 0.231 AC: 35154 AN: 152172 Hom.: 4246 Cov.: 32 AF XY: 0.231 AC XY: 17184 AN XY: 74388

Gnomad4 AFR AF: 0.208

Gnomad4 AMR AF: 0.301

Gnomad4 ASJ AF: 0.166

Gnomad4 EAS AF: 0.248

Gnomad4 SAS AF: 0.334

Gnomad4 FIN AF: 0.197

Gnomad4 NFE AF: 0.231

Gnomad4 OTH AF: 0.234

Alfa AF: 0.226 Hom.: 507

Bravo AF: 0.234

Asia WGS AF: 0.348 AC: 1207 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	10
DANN	Benign	0.79

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: rs1472050; hg19: chr10-106494771;