Genetic Variant SORCS3:p.Gly86* (chr10-104641583-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_014978.3(SORCS3):c.256G>T(p.Gly86*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000075 in 1,333,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

SORCS3
NM_014978.3 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.129

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS3	NM_014978.3 link	c.256G>T	p.Gly86*	stop_gained	Exon 1 of 27	ENST00000369701.8	NP_055793.1	Q9UPU3Q86XB2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8 link	c.256G>T	p.Gly86*	stop_gained	Exon 1 of 27	1	NM_014978.3	ENSP00000358715.3		Q9UPU3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

80322

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.50e-7

AC:

AN:

1333464

Hom.:

Cov.:

AF XY:

0.00000152

AC XY:

AN XY:

656726

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26638

American (AMR)

AF:

0.00

AC:

AN:

28522

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22710

East Asian (EAS)

AF:

0.00

AC:

AN:

30652

South Asian (SAS)

AF:

0.00

AC:

AN:

73130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32678

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4150

European-Non Finnish (NFE)

AF:

9.44e-7

AC:

AN:

1059474

Other (OTH)

AF:

0.00

AC:

AN:

55510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Benign

0.96

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.14

PhyloP100

-0.13

Vest4

0.086

GERP RS

0.55

PromoterAI

0.072

Neutral

(source)

Mutation Taster

=15/185

disease causing (fs/PTC)

(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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10-104641583-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over