rs791116

Variant names:

• chr10-105098584-C-T
• rs791116
• NM_014978.3:c.1094-6813C>T

Variant summary

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

The NM_014978.3(SORCS3):​c.1094-6813C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 152,120 control chromosomes in the GnomAD database, including 2,117 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 0.16 (2117 hom., cov: 32)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0600
• Publications: 1 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=-0.61).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.1094-6813C>T		intron_variant	Intron 6 of 26	ENST00000369701.8	NP_055793.1
SORCS3	XM_011539542.2	c.26-6813C>T		intron_variant	Intron 2 of 22		XP_011537844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8	c.1094-6813C>T		intron_variant	Intron 6 of 26	1	NM_014978.3	ENSP00000358715.3

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24126 AN: 152002 Hom.: 2112 Cov.: 32

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0636

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.172

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

GnomAD4 genome AF: 0.159 AC: 24150 AN: 152120 Hom.: 2117 Cov.: 32 AF XY: 0.158 AC XY: 11715 AN XY: 74364

African (AFR) AF: 0.157 AC: 6524 AN: 41510

American (AMR) AF: 0.118 AC: 1798 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 555 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5186

South Asian (SAS) AF: 0.0635 AC: 306 AN: 4822

European-Finnish (FIN) AF: 0.256 AC: 2707 AN: 10572

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.173 AC: 11731 AN: 67968

Other (OTH) AF: 0.171 AC: 360 AN: 2110

Alfa AF: 0.167 Hom.: 6777

Bravo AF: 0.150

Asia WGS AF: 0.0470 AC: 164 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Benign	0.88
PhyloP100		0.060
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: rs791116; hg19: chr10-106858342;