NM_014978.3:c.695+8651G>A

Variant names:

• chr10-104851510-G-A
• rs1021362
• NM_014978.3:c.695+8651G>A

Variant summary

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

The NM_014978.3(SORCS3):​c.695+8651G>A variant causes a intron change. The variant allele was found at a frequency of 0.732 in 151,834 control chromosomes in the GnomAD database, including 41,671 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 0.73 (41671 hom., cov: 32)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.96
• Publications: 5 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=-0.64).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.874 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.695+8651G>A		intron_variant	Intron 2 of 26	ENST00000369701.8	NP_055793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8	c.695+8651G>A		intron_variant	Intron 2 of 26	1	NM_014978.3	ENSP00000358715.3

Frequencies

GnomAD3 genomes AF: 0.732 AC: 111114 AN: 151716 Hom.: 41624 Cov.: 32

Gnomad AFR AF: 0.881

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.739

Gnomad ASJ AF: 0.749

Gnomad EAS AF: 0.857

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.727

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.641

Gnomad OTH AF: 0.735

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

GnomAD4 genome AF: 0.732 AC: 111210 AN: 151834 Hom.: 41671 Cov.: 32 AF XY: 0.733 AC XY: 54354 AN XY: 74168

African (AFR) AF: 0.882 AC: 36583 AN: 41500

American (AMR) AF: 0.738 AC: 11262 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.749 AC: 2599 AN: 3468

East Asian (EAS) AF: 0.856 AC: 4407 AN: 5146

South Asian (SAS) AF: 0.578 AC: 2785 AN: 4816

European-Finnish (FIN) AF: 0.727 AC: 7627 AN: 10488

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.641 AC: 43508 AN: 67858

Other (OTH) AF: 0.730 AC: 1537 AN: 2106

Alfa AF: 0.681 Hom.: 45198

Bravo AF: 0.747

Asia WGS AF: 0.701 AC: 2440 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Benign	0.33
PhyloP100		4.0
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: rs1021362; hg19: chr10-106611268;