10-104641717-G-A

Variant names:

• chr10-104641717-G-A
• rs770466925
• NM_014978.3:c.390G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_014978.3(SORCS3):​c.390G>A​(p.Arg130Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.0000036 in 1,389,676 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: SORCS3 NM_014978.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.29
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.390G>A	p.Arg130Arg	synonymous_variant	Exon 1 of 27	ENST00000369701.8	NP_055793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8	c.390G>A	p.Arg130Arg	synonymous_variant	Exon 1 of 27	1	NM_014978.3	ENSP00000358715.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000360 AC: 5 AN: 1389676 Hom.: 0 Cov.: 32 AF XY: 0.00000438 AC XY: 3 AN XY: 685308

African (AFR) AF: 0.00 AC: 0 AN: 31242

American (AMR) AF: 0.00 AC: 0 AN: 35348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24908

East Asian (EAS) AF: 0.00 AC: 0 AN: 35544

South Asian (SAS) AF: 0.00 AC: 0 AN: 78764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4716

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1077066

Other (OTH) AF: 0.0000173 AC: 1 AN: 57672

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	13
DANN	Benign	0.76
PhyloP100		4.3
PromoterAI		-0.028	Neutral

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: rs770466925; hg19: chr10-106401475;