chr10-105187431-T-C

Variant names:

• chr10-105187431-T-C
• rs1953071
• NM_014978.3:c.2009+9258T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_014978.3(SORCS3):​c.2009+9258T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 152,052 control chromosomes in the GnomAD database, including 4,519 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 0.24 (4519 hom., cov: 32)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014978.3. 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.2009+9258T>C		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.2009+9258T>C		intron	N/A	ENSP00000358715.3
	SORCS3	ENST00000393176.2	TSL:5	c.344+9258T>C		intron	N/A	ENSP00000376876.2

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37134 AN: 151934 Hom.: 4509 Cov.: 32

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.242

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

GnomAD4 genome AF: 0.244 AC: 37172 AN: 152052 Hom.: 4519 Cov.: 32 AF XY: 0.245 AC XY: 18212 AN XY: 74330

African (AFR) AF: 0.248 AC: 10294 AN: 41478

American (AMR) AF: 0.241 AC: 3679 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 687 AN: 3466

East Asian (EAS) AF: 0.318 AC: 1643 AN: 5164

South Asian (SAS) AF: 0.304 AC: 1465 AN: 4816

European-Finnish (FIN) AF: 0.212 AC: 2242 AN: 10576

Middle Eastern (MID) AF: 0.247 AC: 72 AN: 292

European-Non Finnish (NFE) AF: 0.241 AC: 16382 AN: 67972

Other (OTH) AF: 0.250 AC: 524 AN: 2100

Alfa AF: 0.157 Hom.: 385

Bravo AF: 0.247

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Benign	0.74
PhyloP100		1.1
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: rs1953071; hg19: chr10-106947189;