10-104853659-G-T

Variant names:

• chr10-104853659-G-T
• rs7895087
• NM_014978.3:c.695+10800G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014978.3(SORCS3):​c.695+10800G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 152,004 control chromosomes in the GnomAD database, including 26,954 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 0.59 (26954 hom., cov: 32)
• Consequence: SORCS3 NM_014978.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.84
• Publications: 6 publications found

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]

SORCS3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.823 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014978.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORCS3	NM_014978.3	MANE Select	c.695+10800G>T		intron	N/A	NP_055793.1	Q9UPU3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORCS3	ENST00000369701.8	TSL:1 MANE Select	c.695+10800G>T		intron	N/A	ENSP00000358715.3	Q9UPU3

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89772 AN: 151884 Hom.: 26927 Cov.: 32

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.665

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.844

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.693

Gnomad MID AF: 0.600

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.611

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

GnomAD4 genome AF: 0.591 AC: 89848 AN: 152004 Hom.: 26954 Cov.: 32 AF XY: 0.594 AC XY: 44147 AN XY: 74300

African (AFR) AF: 0.529 AC: 21905 AN: 41438

American (AMR) AF: 0.669 AC: 10232 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 2267 AN: 3470

East Asian (EAS) AF: 0.844 AC: 4362 AN: 5170

South Asian (SAS) AF: 0.485 AC: 2336 AN: 4818

European-Finnish (FIN) AF: 0.693 AC: 7317 AN: 10562

Middle Eastern (MID) AF: 0.624 AC: 181 AN: 290

European-Non Finnish (NFE) AF: 0.579 AC: 39365 AN: 67950

Other (OTH) AF: 0.606 AC: 1278 AN: 2110

Alfa AF: 0.588 Hom.: 44084

Bravo AF: 0.594

Asia WGS AF: 0.617 AC: 2147 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.25
DANN	Benign	0.49
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7895087; hg19: chr10-106613417;