10-105230641-A-G

Variant names:

• chr10-105230641-A-G
• rs749304
• NM_014978.3:c.2868+7392A>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.2868+7392A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 152,042 control chromosomes in the GnomAD database, including 4,108 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 0.23 (4108 hom., cov: 32)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.929
• Publications: 2 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.2868+7392A>G		intron_variant	Intron 20 of 26	ENST00000369701.8	NP_055793.1
SORCS3	XM_011539542.2	c.1800+7392A>G		intron_variant	Intron 16 of 22		XP_011537844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8	c.2868+7392A>G		intron_variant	Intron 20 of 26	1	NM_014978.3	ENSP00000358715.3

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35461 AN: 151924 Hom.: 4099 Cov.: 32

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.256

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.226

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

GnomAD4 genome AF: 0.233 AC: 35499 AN: 152042 Hom.: 4108 Cov.: 32 AF XY: 0.233 AC XY: 17316 AN XY: 74322

African (AFR) AF: 0.217 AC: 9011 AN: 41496

American (AMR) AF: 0.235 AC: 3591 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 673 AN: 3468

East Asian (EAS) AF: 0.200 AC: 1030 AN: 5146

South Asian (SAS) AF: 0.303 AC: 1459 AN: 4808

European-Finnish (FIN) AF: 0.204 AC: 2165 AN: 10592

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.247 AC: 16786 AN: 67946

Other (OTH) AF: 0.233 AC: 491 AN: 2108

Alfa AF: 0.242 Hom.: 803

Bravo AF: 0.235

Asia WGS AF: 0.312 AC: 1084 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.5
DANN	Benign	0.56
PhyloP100		-0.93
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: rs749304; hg19: chr10-106990399;