rs791123

Variant names:

• chr10-105146900-A-G
• rs791123
• NM_014978.3:c.1303-717A>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.1303-717A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 152,008 control chromosomes in the GnomAD database, including 20,959 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 0.52 (20959 hom., cov: 32)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.743
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.1303-717A>G		intron_variant	Intron 8 of 26	ENST00000369701.8	NP_055793.1
SORCS3	XM_011539542.2	c.235-717A>G		intron_variant	Intron 4 of 22		XP_011537844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8	c.1303-717A>G		intron_variant	Intron 8 of 26	1	NM_014978.3	ENSP00000358715.3

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79122 AN: 151890 Hom.: 20938 Cov.: 32

Gnomad AFR AF: 0.484

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.521

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.509

Gnomad FIN AF: 0.487

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.541

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

GnomAD4 genome AF: 0.521 AC: 79197 AN: 152008 Hom.: 20959 Cov.: 32 AF XY: 0.517 AC XY: 38378 AN XY: 74290

African (AFR) AF: 0.484 AC: 20070 AN: 41450

American (AMR) AF: 0.558 AC: 8509 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 1808 AN: 3468

East Asian (EAS) AF: 0.333 AC: 1717 AN: 5162

South Asian (SAS) AF: 0.508 AC: 2453 AN: 4828

European-Finnish (FIN) AF: 0.487 AC: 5146 AN: 10572

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.552 AC: 37548 AN: 67964

Other (OTH) AF: 0.546 AC: 1153 AN: 2110

Alfa AF: 0.538 Hom.: 3347

Bravo AF: 0.522

Asia WGS AF: 0.502 AC: 1746 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.8
DANN	Benign	0.81
PhyloP100		-0.74
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: rs791123; hg19: chr10-106906658;