10-104843328-T-G

Variant names:

• chr10-104843328-T-G
• rs1027190
• NM_014978.3:c.695+469T>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.695+469T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.718 in 152,022 control chromosomes in the GnomAD database, including 39,977 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 0.72 (39977 hom., cov: 31)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.841 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.695+469T>G		intron_variant	Intron 2 of 26	ENST00000369701.8	NP_055793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8	c.695+469T>G		intron_variant	Intron 2 of 26	1	NM_014978.3	ENSP00000358715.3

Frequencies

GnomAD3 genomes AF: 0.718 AC: 109044 AN: 151904 Hom.: 39938 Cov.: 31

Gnomad AFR AF: 0.848

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.726

Gnomad ASJ AF: 0.749

Gnomad EAS AF: 0.859

Gnomad SAS AF: 0.575

Gnomad FIN AF: 0.726

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.633

Gnomad OTH AF: 0.723

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

GnomAD4 genome AF: 0.718 AC: 109137 AN: 152022 Hom.: 39977 Cov.: 31 AF XY: 0.719 AC XY: 53420 AN XY: 74286

African (AFR) AF: 0.848 AC: 35191 AN: 41498

American (AMR) AF: 0.726 AC: 11089 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.749 AC: 2598 AN: 3470

East Asian (EAS) AF: 0.859 AC: 4427 AN: 5156

South Asian (SAS) AF: 0.574 AC: 2762 AN: 4814

European-Finnish (FIN) AF: 0.726 AC: 7664 AN: 10556

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.633 AC: 42980 AN: 67930

Other (OTH) AF: 0.720 AC: 1522 AN: 2114

Alfa AF: 0.634 Hom.: 3093

Bravo AF: 0.731

Asia WGS AF: 0.709 AC: 2468 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.58
DANN	Benign	0.41
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: rs1027190; hg19: chr10-106603086;