10-104818878-G-T

Variant names:

• chr10-104818878-G-T
• rs2491388
• NM_014978.3:c.628-23914G>T

Variant summary

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

The NM_014978.3(SORCS3):​c.628-23914G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.755 in 151,966 control chromosomes in the GnomAD database, including 43,352 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 0.75 (43352 hom., cov: 31)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.752
• 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.628-23914G>T		intron_variant	Intron 1 of 26	ENST00000369701.8	NP_055793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8	c.628-23914G>T		intron_variant	Intron 1 of 26	1	NM_014978.3	ENSP00000358715.3

Frequencies

GnomAD3 genomes AF: 0.755 AC: 114640 AN: 151850 Hom.: 43327 Cov.: 31

Gnomad AFR AF: 0.771

Gnomad AMI AF: 0.754

Gnomad AMR AF: 0.795

Gnomad ASJ AF: 0.734

Gnomad EAS AF: 0.834

Gnomad SAS AF: 0.780

Gnomad FIN AF: 0.797

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.722

Gnomad OTH AF: 0.772

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

GnomAD4 genome AF: 0.755 AC: 114714 AN: 151966 Hom.: 43352 Cov.: 31 AF XY: 0.758 AC XY: 56311 AN XY: 74254

African (AFR) AF: 0.771 AC: 31948 AN: 41448

American (AMR) AF: 0.795 AC: 12143 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.734 AC: 2547 AN: 3468

East Asian (EAS) AF: 0.834 AC: 4302 AN: 5158

South Asian (SAS) AF: 0.780 AC: 3733 AN: 4788

European-Finnish (FIN) AF: 0.797 AC: 8395 AN: 10536

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.722 AC: 49111 AN: 67978

Other (OTH) AF: 0.772 AC: 1630 AN: 2112

Alfa AF: 0.739 Hom.: 5160

Bravo AF: 0.758

Asia WGS AF: 0.789 AC: 2744 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.39
DANN	Benign	0.51
PhyloP100		-0.75
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: rs2491388; hg19: chr10-106578636;