rs1484247

Positions:

• chr10-105261156-A-C
• chr10-105261156-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014978.3(SORCS3):​c.3444-1175A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 152,096 control chromosomes in the GnomAD database, including 9,541 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 0.32 (9541 hom., cov: 32)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0850

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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.3444-1175A>C		intron_variant		ENST00000369701.8	NP_055793.1
SORCS3	XM_011539542.2	c.2376-1175A>C		intron_variant			XP_011537844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8	c.3444-1175A>C		intron_variant		1	NM_014978.3	ENSP00000358715	P1

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48315 AN: 151978 Hom.: 9547 Cov.: 32

Gnomad AFR AF: 0.0886

Gnomad AMI AF: 0.346

Gnomad AMR AF: 0.368

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.688

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.486

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.367

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

GnomAD4 genome AF: 0.318 AC: 48303 AN: 152096 Hom.: 9541 Cov.: 32 AF XY: 0.327 AC XY: 24286 AN XY: 74354

Gnomad4 AFR AF: 0.0884

Gnomad4 AMR AF: 0.368

Gnomad4 ASJ AF: 0.450

Gnomad4 EAS AF: 0.686

Gnomad4 SAS AF: 0.381

Gnomad4 FIN AF: 0.486

Gnomad4 NFE AF: 0.379

Gnomad4 OTH AF: 0.363

Alfa AF: 0.377 Hom.: 14842

Bravo AF: 0.301

Asia WGS AF: 0.429 AC: 1491 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.13
DANN	Benign	0.38

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: rs1484247; hg19: chr10-107020914;