10-104950416-T-C

Variant names:

• chr10-104950416-T-C
• rs7096635
• NM_014978.3:c.796-26919T>C

Variant summary

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

The NM_014978.3(SORCS3):​c.796-26919T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 151,956 control chromosomes in the GnomAD database, including 6,248 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 0.27 (6248 hom., cov: 32)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42
• 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.796-26919T>C		intron_variant	Intron 3 of 26	ENST00000369701.8	NP_055793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8	c.796-26919T>C		intron_variant	Intron 3 of 26	1	NM_014978.3	ENSP00000358715.3

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41172 AN: 151838 Hom.: 6233 Cov.: 32

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.261

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

GnomAD4 genome AF: 0.271 AC: 41223 AN: 151956 Hom.: 6248 Cov.: 32 AF XY: 0.270 AC XY: 20054 AN XY: 74250

African (AFR) AF: 0.415 AC: 17191 AN: 41416

American (AMR) AF: 0.199 AC: 3039 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 878 AN: 3464

East Asian (EAS) AF: 0.247 AC: 1276 AN: 5166

South Asian (SAS) AF: 0.394 AC: 1894 AN: 4810

European-Finnish (FIN) AF: 0.147 AC: 1552 AN: 10546

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.215 AC: 14593 AN: 67966

Other (OTH) AF: 0.268 AC: 566 AN: 2110

Alfa AF: 0.172 Hom.: 551

Bravo AF: 0.278

Asia WGS AF: 0.380 AC: 1319 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.5
DANN	Benign	0.63
PhyloP100		-1.4
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: rs7096635; hg19: chr10-106710174;