rs768731

Variant names:

• chr10-105074692-C-A
• rs768731
• NM_014978.3:c.1029-15083C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-105074692-C-A
• chr10-105074692-C-G
• chr10-105074692-C-T

Variant summary

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

The NM_014978.3(SORCS3):​c.1029-15083C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 152,052 control chromosomes in the GnomAD database, including 36,384 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 0.69 (36384 hom., cov: 32)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56
• Publications: 4 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.1029-15083C>A		intron_variant	Intron 5 of 26	ENST00000369701.8	NP_055793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8	c.1029-15083C>A		intron_variant	Intron 5 of 26	1	NM_014978.3	ENSP00000358715.3

Frequencies

GnomAD3 genomes AF: 0.690 AC: 104809 AN: 151934 Hom.: 36366 Cov.: 32

Gnomad AFR AF: 0.705

Gnomad AMI AF: 0.592

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.838

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.797

Gnomad MID AF: 0.675

Gnomad NFE AF: 0.674

Gnomad OTH AF: 0.696

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

GnomAD4 genome AF: 0.690 AC: 104873 AN: 152052 Hom.: 36384 Cov.: 32 AF XY: 0.693 AC XY: 51487 AN XY: 74320

African (AFR) AF: 0.706 AC: 29267 AN: 41472

American (AMR) AF: 0.612 AC: 9358 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 2434 AN: 3466

East Asian (EAS) AF: 0.837 AC: 4307 AN: 5146

South Asian (SAS) AF: 0.642 AC: 3090 AN: 4810

European-Finnish (FIN) AF: 0.797 AC: 8429 AN: 10576

Middle Eastern (MID) AF: 0.678 AC: 198 AN: 292

European-Non Finnish (NFE) AF: 0.674 AC: 45793 AN: 67982

Other (OTH) AF: 0.691 AC: 1457 AN: 2110

Alfa AF: 0.642 Hom.: 11543

Bravo AF: 0.680

Asia WGS AF: 0.679 AC: 2361 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.20
DANN	Benign	0.64
PhyloP100		-1.6
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: rs768731; hg19: chr10-106834450;