rs757347409

Variant names:

• chr10-104641464-C-A
• rs757347409
• NM_014978.3:c.137C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-104641464-C-A
• chr10-104641464-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014978.3(SORCS3):​c.137C>A​(p.Pro46Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000076 in 1,315,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P46L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: SORCS3 NM_014978.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0870
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07393095).

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.137C>A	p.Pro46Gln	missense	Exon 1 of 27	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.137C>A	p.Pro46Gln	missense	Exon 1 of 27	ENSP00000358715.3	Q9UPU3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.60e-7 AC: 1 AN: 1315046 Hom.: 0 Cov.: 31 AF XY: 0.00000154 AC XY: 1 AN XY: 647728

African (AFR) AF: 0.00 AC: 0 AN: 26506

American (AMR) AF: 0.00 AC: 0 AN: 24946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23166

East Asian (EAS) AF: 0.00 AC: 0 AN: 28202

South Asian (SAS) AF: 0.00 AC: 0 AN: 72110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32788

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4048

European-Non Finnish (NFE) AF: 9.53e-7 AC: 1 AN: 1048820

Other (OTH) AF: 0.00 AC: 0 AN: 54460

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Benign	0.80
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.087
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.0060
Sift	Benign	0.14	T
Sift4G	Uncertain	0.025	D
Polyphen		0.0090	B
Vest4		0.21
MutPred		0.20		Loss of glycosylation at P46 (P = 0.0232)
MVP		0.15
MPC		0.33
ClinPred		0.053	T
GERP RS		-1.5
PromoterAI		0.044	Neutral
Varity_R		0.031
gMVP		0.23
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs757347409; hg19: chr10-106401222;