chr10-105055104-G-A

Variant names:

• chr10-105055104-G-A
• rs790726
• NM_014978.3:c.1028+11976G>A

Variant summary

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

The NM_014978.3(SORCS3):​c.1028+11976G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 151,954 control chromosomes in the GnomAD database, including 19,172 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 0.47 (19172 hom., cov: 32)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.185
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.1028+11976G>A		intron_variant	Intron 5 of 26	ENST00000369701.8	NP_055793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8	c.1028+11976G>A		intron_variant	Intron 5 of 26	1	NM_014978.3	ENSP00000358715.3

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70879 AN: 151836 Hom.: 19175 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.652

Gnomad AMR AF: 0.618

Gnomad ASJ AF: 0.514

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.555

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.568

Gnomad OTH AF: 0.478

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

GnomAD4 genome AF: 0.466 AC: 70877 AN: 151954 Hom.: 19172 Cov.: 32 AF XY: 0.472 AC XY: 35030 AN XY: 74226

African (AFR) AF: 0.175 AC: 7250 AN: 41446

American (AMR) AF: 0.618 AC: 9434 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 1782 AN: 3468

East Asian (EAS) AF: 0.690 AC: 3554 AN: 5154

South Asian (SAS) AF: 0.552 AC: 2661 AN: 4820

European-Finnish (FIN) AF: 0.555 AC: 5843 AN: 10528

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.568 AC: 38612 AN: 67950

Other (OTH) AF: 0.473 AC: 1000 AN: 2112

Alfa AF: 0.495 Hom.: 2657

Bravo AF: 0.461

Asia WGS AF: 0.527 AC: 1833 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.48
DANN	Benign	0.35
PhyloP100		-0.18
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: rs790726; hg19: chr10-106814862; COSMIC: COSV63819037;