NM_014978.3:c.695+10713C>A

Variant names:

• chr10-104853572-C-A
• rs7894737
• NM_014978.3:c.695+10713C>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+10713C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 152,022 control chromosomes in the GnomAD database, including 26,963 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 0.59 (26963 hom., cov: 33)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.395
• Publications: 3 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 = 0.825 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014978.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORCS3	NM_014978.3	MANE Select	c.695+10713C>A		intron	N/A	NP_055793.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORCS3	ENST00000369701.8	TSL:1 MANE Select	c.695+10713C>A		intron	N/A	ENSP00000358715.3

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89794 AN: 151902 Hom.: 26937 Cov.: 33

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.846

Gnomad SAS AF: 0.482

Gnomad FIN AF: 0.694

Gnomad MID AF: 0.593

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.611

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

GnomAD4 genome AF: 0.591 AC: 89868 AN: 152022 Hom.: 26963 Cov.: 33 AF XY: 0.594 AC XY: 44167 AN XY: 74304

African (AFR) AF: 0.529 AC: 21925 AN: 41456

American (AMR) AF: 0.669 AC: 10230 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 2266 AN: 3468

East Asian (EAS) AF: 0.846 AC: 4375 AN: 5174

South Asian (SAS) AF: 0.482 AC: 2322 AN: 4820

European-Finnish (FIN) AF: 0.694 AC: 7326 AN: 10560

Middle Eastern (MID) AF: 0.613 AC: 179 AN: 292

European-Non Finnish (NFE) AF: 0.579 AC: 39363 AN: 67944

Other (OTH) AF: 0.606 AC: 1276 AN: 2106

Alfa AF: 0.570 Hom.: 3648

Bravo AF: 0.594

Asia WGS AF: 0.614 AC: 2138 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.60
PhyloP100		-0.40
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: rs7894737; hg19: chr10-106613330;