rs3011669

Positions:

• chr10-105252415-A-G
• chr10-105252415-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.3106-360A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.572 in 152,034 control chromosomes in the GnomAD database, including 25,182 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 0.57 (25182 hom., cov: 33)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00900

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=-0.71).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.3106-360A>G		intron_variant		ENST00000369701.8	NP_055793.1
SORCS3	XM_011539542.2	c.2038-360A>G		intron_variant			XP_011537844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8	c.3106-360A>G		intron_variant		1	NM_014978.3	ENSP00000358715.3

Frequencies

GnomAD3 genomes AF: 0.573 AC: 86976 AN: 151916 Hom.: 25177 Cov.: 33

Gnomad AFR AF: 0.593

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.623

Gnomad EAS AF: 0.750

Gnomad SAS AF: 0.504

Gnomad FIN AF: 0.677

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.549

Gnomad OTH AF: 0.569

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

GnomAD4 genome AF: 0.572 AC: 87012 AN: 152034 Hom.: 25182 Cov.: 33 AF XY: 0.576 AC XY: 42853 AN XY: 74334

Gnomad4 AFR AF: 0.593

Gnomad4 AMR AF: 0.508

Gnomad4 ASJ AF: 0.623

Gnomad4 EAS AF: 0.749

Gnomad4 SAS AF: 0.505

Gnomad4 FIN AF: 0.677

Gnomad4 NFE AF: 0.549

Gnomad4 OTH AF: 0.563

Alfa AF: 0.548 Hom.: 10194

Bravo AF: 0.564

Asia WGS AF: 0.543 AC: 1890 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.2
DANN	Benign	0.74

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: rs3011669; hg19: chr10-107012173;