rs1034178

Variant names:

• chr10-105139663-T-C
• rs1034178
• NM_014978.3:c.1302+177T>C

Variant summary

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

The NM_014978.3(SORCS3):​c.1302+177T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.509 in 151,900 control chromosomes in the GnomAD database, including 19,973 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 0.51 (19973 hom., cov: 31)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0610

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 (AMR) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.1302+177T>C		intron_variant	Intron 8 of 26	ENST00000369701.8	NP_055793.1
SORCS3	XM_011539542.2	c.234+177T>C		intron_variant	Intron 4 of 22		XP_011537844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8	c.1302+177T>C		intron_variant	Intron 8 of 26	1	NM_014978.3	ENSP00000358715.3

Frequencies

GnomAD3 genomes AF: 0.509 AC: 77246 AN: 151780 Hom.: 19952 Cov.: 31

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.671

Gnomad AMR AF: 0.551

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.334

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.516

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

GnomAD4 genome AF: 0.509 AC: 77315 AN: 151900 Hom.: 19973 Cov.: 31 AF XY: 0.504 AC XY: 37450 AN XY: 74232

Gnomad4 AFR AF: 0.464

Gnomad4 AMR AF: 0.551

Gnomad4 ASJ AF: 0.510

Gnomad4 EAS AF: 0.335

Gnomad4 SAS AF: 0.452

Gnomad4 FIN AF: 0.488

Gnomad4 NFE AF: 0.545

Gnomad4 OTH AF: 0.521

Alfa AF: 0.541 Hom.: 3791

Bravo AF: 0.512

Asia WGS AF: 0.474 AC: 1647 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.1
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: rs1034178; hg19: chr10-106899421;