10-105112348-T-G

Variant names:

• chr10-105112348-T-G
• rs11192320
• NM_014978.3:c.1212+6833T>G

Variant summary

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

The ENST00000369701.8(SORCS3):​c.1212+6833T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 152,106 control chromosomes in the GnomAD database, including 3,030 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 0.19 (3030 hom., cov: 32)
• Consequence: SORCS3 ENST00000369701.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.771
• Publications: 4 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000369701.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORCS3	NM_014978.3	MANE Select	c.1212+6833T>G		intron	N/A	NP_055793.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORCS3	ENST00000369701.8	TSL:1 MANE Select	c.1212+6833T>G		intron	N/A	ENSP00000358715.3

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29243 AN: 151988 Hom.: 3025 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.370

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.182

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

GnomAD4 genome AF: 0.192 AC: 29276 AN: 152106 Hom.: 3030 Cov.: 32 AF XY: 0.188 AC XY: 13996 AN XY: 74334

African (AFR) AF: 0.149 AC: 6180 AN: 41492

American (AMR) AF: 0.242 AC: 3691 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 777 AN: 3472

East Asian (EAS) AF: 0.168 AC: 866 AN: 5170

South Asian (SAS) AF: 0.192 AC: 921 AN: 4802

European-Finnish (FIN) AF: 0.119 AC: 1262 AN: 10582

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14805 AN: 68004

Other (OTH) AF: 0.182 AC: 385 AN: 2112

Alfa AF: 0.199 Hom.: 1713

Bravo AF: 0.196

Asia WGS AF: 0.187 AC: 650 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.35
DANN	Benign	0.45
PhyloP100		-0.77
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: rs11192320; hg19: chr10-106872106;