rs1361800

Variant names:

• chr10-105052358-T-G
• rs1361800
• NM_014978.3:c.1028+9230T>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.1028+9230T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 152,212 control chromosomes in the GnomAD database, including 1,752 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 0.13 (1752 hom., cov: 33)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62
• Publications: 6 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.1028+9230T>G		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.1028+9230T>G		intron_variant	Intron 5 of 26	1	NM_014978.3	ENSP00000358715.3

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20529 AN: 152094 Hom.: 1749 Cov.: 33

Gnomad AFR AF: 0.0351

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.0949

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.128

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

GnomAD4 genome AF: 0.135 AC: 20534 AN: 152212 Hom.: 1752 Cov.: 33 AF XY: 0.136 AC XY: 10118 AN XY: 74394

African (AFR) AF: 0.0350 AC: 1456 AN: 41566

American (AMR) AF: 0.133 AC: 2036 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0949 AC: 329 AN: 3468

East Asian (EAS) AF: 0.114 AC: 588 AN: 5170

South Asian (SAS) AF: 0.194 AC: 937 AN: 4826

European-Finnish (FIN) AF: 0.181 AC: 1918 AN: 10586

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.189 AC: 12864 AN: 68002

Other (OTH) AF: 0.127 AC: 268 AN: 2110

Alfa AF: 0.174 Hom.: 1451

Bravo AF: 0.125

Asia WGS AF: 0.144 AC: 501 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.3
DANN	Benign	0.50
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: rs1361800; hg19: chr10-106812116;