Genetic Variant NM_014978.3:c.2009+9258T>C (chr10-105187431-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_014978.3(SORCS3):c.2009+9258T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 152,052 control chromosomes in the GnomAD database, including 4,519 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 0.24 ( 4519 hom., cov: 32)

Consequence

SORCS3
NM_014978.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.10

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS3	NM_014978.3 link	c.2009+9258T>C		intron_variant	Intron 14 of 26	ENST00000369701.8	NP_055793.1	Q9UPU3Q86XB2
SORCS3	XM_011539542.2 link	c.941+9258T>C		intron_variant	Intron 10 of 22		XP_011537844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8 link	c.2009+9258T>C		intron_variant	Intron 14 of 26	1	NM_014978.3	ENSP00000358715.3		Q9UPU3
SORCS3	ENST00000393176.2 link	c.344+9258T>C		intron_variant	Intron 4 of 4	5		ENSP00000376876.2		Q5CAJ2

Frequencies

GnomAD3 genomes

AF:

0.244

AC:

37134

AN:

151934

Hom.:

4509

Cov.:

show subpopulations

Gnomad AFR

AF:

0.248

Gnomad AMI

AF:

0.202

Gnomad AMR

AF:

0.241

Gnomad ASJ

AF:

0.198

Gnomad EAS

AF:

0.317

Gnomad SAS

AF:

0.304

Gnomad FIN

AF:

0.212

Gnomad MID

AF:

0.252

Gnomad NFE

AF:

0.241

Gnomad OTH

AF:

0.242

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

GnomAD4 genome

AF:

0.244

AC:

37172

AN:

152052

Hom.:

4519

Cov.:

AF XY:

0.245

AC XY:

18212

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.248

AC:

10294

AN:

41478

American (AMR)

AF:

0.241

AC:

3679

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.198

AC:

687

AN:

3466

East Asian (EAS)

AF:

0.318

AC:

1643

AN:

5164

South Asian (SAS)

AF:

0.304

AC:

1465

AN:

4816

European-Finnish (FIN)

AF:

0.212

AC:

2242

AN:

10576

Middle Eastern (MID)

AF:

0.247

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.241

AC:

16382

AN:

67972

Other (OTH)

AF:

0.250

AC:

524

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1436

2872

4307

5743

7179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

398

796

1194

1592

1990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.157

Hom.:

385

Bravo

AF:

0.247

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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