10-104818878-G-T

Position:

• chr10-104818878-G-T

Variant summary

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

The ENST00000369701.8(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 ENST00000369701.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.752

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=-0.96).
• 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/exons	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.628-23914G>T		intron_variant		ENST00000369701.8	NP_055793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8	c.628-23914G>T		intron_variant		1	NM_014978.3	ENSP00000358715	P1

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

Gnomad4 AFR AF: 0.771

Gnomad4 AMR AF: 0.795

Gnomad4 ASJ AF: 0.734

Gnomad4 EAS AF: 0.834

Gnomad4 SAS AF: 0.780

Gnomad4 FIN AF: 0.797

Gnomad4 NFE AF: 0.722

Gnomad4 OTH AF: 0.772

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

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: rs2491388; hg19: chr10-106578636;