rs790726

Positions:

• chr10-105055104-G-A
• chr10-105055104-G-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.1028+11976G>A		intron_variant		ENST00000369701.8	NP_055793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8	c.1028+11976G>A		intron_variant		1	NM_014978.3	ENSP00000358715	P1

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

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.618

Gnomad4 ASJ AF: 0.514

Gnomad4 EAS AF: 0.690

Gnomad4 SAS AF: 0.552

Gnomad4 FIN AF: 0.555

Gnomad4 NFE AF: 0.568

Gnomad4 OTH AF: 0.473

Alfa AF: 0.508 Hom.: 2642

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs790726; hg19: chr10-106814862; COSMIC: COSV63819037;