Genetic Variant SORCS3:p.Pro46Leu (chr10-104641464-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_014978.3(SORCS3):c.137C>T(p.Pro46Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,467,174 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

SORCS3
NM_014978.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0870

Publications

0 publications found

Variant links:

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

SORCS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03552887).

BS2

High AC in GnomAdExome4 at 20 AD gene.

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>T	p.Pro46Leu	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>T	p.Pro46Leu	missense	Exon 1 of 27	ENSP00000358715.3	Q9UPU3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000686

AC:

AN:

72928

AF XY:

0.0000948

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000400

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000371

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000152

AC:

AN:

1315046

Hom.:

Cov.:

AF XY:

0.0000216

AC XY:

AN XY:

647728

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26506

American (AMR)

AF:

0.00

AC:

AN:

24946

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23166

East Asian (EAS)

AF:

0.000248

AC:

AN:

28202

South Asian (SAS)

AF:

0.0000555

AC:

AN:

72110

European-Finnish (FIN)

AF:

0.0000915

AC:

AN:

32788

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4048

European-Non Finnish (NFE)

AF:

0.00000381

AC:

AN:

1048820

Other (OTH)

AF:

0.0000367

AC:

AN:

54460

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74382

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41568

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67954

Other (OTH)

AF:

0.00

AC:

AN:

2108

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000405

AC:

Asia WGS

AF:

0.000583

AC:

AN:

3446

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.014

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.52

M_CAP

Benign

0.072

MetaRNN

Benign

0.036

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

PhyloP100

-0.087

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.85

REVEL

Benign

0.011

Sift

Benign

0.95

Sift4G

Uncertain

0.035

Polyphen

0.0

Vest4

0.072

MutPred

0.31

Loss of glycosylation at P46 (P = 0.0232)

MVP

0.27

MPC

0.35

ClinPred

0.031

GERP RS

-1.5

PromoterAI

-0.0051

Neutral

(source)

Varity_R

0.027

gMVP

0.13

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over