rs790640

Positions:

• chr10-105023793-G-A

Variant summary

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

The NM_014978.3(SORCS3):​c.955-19262G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 151,880 control chromosomes in the GnomAD database, including 2,931 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 0.20 (2931 hom., cov: 31)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.192

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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORCS3	NM_014978.3	c.955-19262G>A		intron_variant		ENST00000369701.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORCS3	ENST00000369701.8	c.955-19262G>A		intron_variant		1	NM_014978.3	P1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29640 AN: 151762 Hom.: 2922 Cov.: 31

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.181

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

GnomAD4 genome AF: 0.195 AC: 29669 AN: 151880 Hom.: 2931 Cov.: 31 AF XY: 0.195 AC XY: 14469 AN XY: 74204

Gnomad4 AFR AF: 0.227

Gnomad4 AMR AF: 0.158

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.148

Gnomad4 SAS AF: 0.248

Gnomad4 FIN AF: 0.177

Gnomad4 NFE AF: 0.193

Gnomad4 OTH AF: 0.186

Alfa AF: 0.187 Hom.: 5599

Bravo AF: 0.193

Asia WGS AF: 0.257 AC: 893 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.5
DANN	Benign	0.64

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: rs790640; hg19: chr10-106783551; COSMIC: COSV63821602;