rs10509784

Variant names:

• chr10-105146129-C-G
• rs10509784
• NM_014978.3:c.1303-1488C>G

Variant summary

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

The NM_014978.3(SORCS3):​c.1303-1488C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0395 in 152,146 control chromosomes in the GnomAD database, including 180 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 0.039 (180 hom., cov: 32)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.851
• Publications: 1 publications found

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]

SORCS3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.1303-1488C>G		intron_variant	Intron 8 of 26	ENST00000369701.8	NP_055793.1
SORCS3	XM_011539542.2	c.235-1488C>G		intron_variant	Intron 4 of 22		XP_011537844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8	c.1303-1488C>G		intron_variant	Intron 8 of 26	1	NM_014978.3	ENSP00000358715.3

Frequencies

GnomAD3 genomes AF: 0.0394 AC: 5990 AN: 152028 Hom.: 182 Cov.: 32

Gnomad AFR AF: 0.0616

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0588

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.0674

Gnomad FIN AF: 0.0202

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.0411

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

GnomAD4 genome AF: 0.0395 AC: 6009 AN: 152146 Hom.: 180 Cov.: 32 AF XY: 0.0408 AC XY: 3036 AN XY: 74408

African (AFR) AF: 0.0621 AC: 2576 AN: 41508

American (AMR) AF: 0.0268 AC: 409 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0588 AC: 204 AN: 3468

East Asian (EAS) AF: 0.156 AC: 808 AN: 5164

South Asian (SAS) AF: 0.0660 AC: 318 AN: 4820

European-Finnish (FIN) AF: 0.0202 AC: 215 AN: 10618

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0202 AC: 1374 AN: 67980

Other (OTH) AF: 0.0436 AC: 92 AN: 2112

Alfa AF: 0.0299 Hom.: 13

Bravo AF: 0.0412

Asia WGS AF: 0.133 AC: 461 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.4
DANN	Benign	0.77
PhyloP100		-0.85
Mutation Taster		=100/0	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: rs10509784; hg19: chr10-106905887;