chr10-105187431-T-C

Position:

• chr10-105187431-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_014978.3(SORCS3):​c.2009+9258T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 152,052 control chromosomes in the GnomAD database, including 4,519 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 0.24 (4519 hom., cov: 32)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.2009+9258T>C		intron_variant		ENST00000369701.8	NP_055793.1
SORCS3	XM_011539542.2	c.941+9258T>C		intron_variant			XP_011537844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8	c.2009+9258T>C		intron_variant		1	NM_014978.3	ENSP00000358715.3
SORCS3	ENST00000393176.2	c.344+9258T>C		intron_variant		5		ENSP00000376876.2

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37134 AN: 151934 Hom.: 4509 Cov.: 32

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.242

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

GnomAD4 genome AF: 0.244 AC: 37172 AN: 152052 Hom.: 4519 Cov.: 32 AF XY: 0.245 AC XY: 18212 AN XY: 74330

Gnomad4 AFR AF: 0.248

Gnomad4 AMR AF: 0.241

Gnomad4 ASJ AF: 0.198

Gnomad4 EAS AF: 0.318

Gnomad4 SAS AF: 0.304

Gnomad4 FIN AF: 0.212

Gnomad4 NFE AF: 0.241

Gnomad4 OTH AF: 0.250

Alfa AF: 0.157 Hom.: 385

Bravo AF: 0.247

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Benign	0.74

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: rs1953071; hg19: chr10-106947189;