rs2298813

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003105.6(SORL1):c.1582G>A(p.Ala528Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.057 in 1,612,676 control chromosomes in the GnomAD database, including 3,299 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.068 ( 437 hom., cov: 32)

Exomes 𝑓: 0.056 ( 2862 hom. )

Consequence

SORL1
NM_003105.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 9.30

Publications

60 publications found

Variant links:

Genes affected

SORL1 (HGNC:11185): (sortilin related receptor 1) This gene encodes a mosaic protein that belongs to at least two families: the vacuolar protein sorting 10 (VPS10) domain-containing receptor family, and the low density lipoprotein receptor (LDLR) family. The encoded protein also contains fibronectin type III repeats and an epidermal growth factor repeat. The encoded preproprotein is proteolytically processed to generate the mature receptor, which likely plays roles in endocytosis and sorting. Mutations in this gene may be associated with Alzheimer's disease. [provided by RefSeq, Feb 2016]

SORL1 Gene-Disease associations (from GenCC):

early-onset autosomal dominant Alzheimer disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SORL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025209486).

BP6

Variant 11-121522975-G-A is Benign according to our data. Variant chr11-121522975-G-A is described in ClinVar as Benign. ClinVar VariationId is 1209925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6 link	c.1582G>A	p.Ala528Thr	missense_variant	Exon 11 of 48	ENST00000260197.12	NP_003096.2	Q92673A0A024R3H2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12 link	c.1582G>A	p.Ala528Thr	missense_variant	Exon 11 of 48	1	NM_003105.6	ENSP00000260197.6		Q92673
SORL1	ENST00000532451.1 link	n.1534G>A		non_coding_transcript_exon_variant	Exon 11 of 15	1

Frequencies

GnomAD3 genomes

AF:

0.0684

AC:

10404

AN:

152122

Hom.:

436

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0960

Gnomad AMI

AF:

0.0625

Gnomad AMR

AF:

0.0887

Gnomad ASJ

AF:

0.0326

Gnomad EAS

AF:

0.125

Gnomad SAS

AF:

0.117

Gnomad FIN

AF:

0.0441

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0452

Gnomad OTH

AF:

0.0670

GnomAD2 exomes

AF:

0.0724

AC:

18203

AN:

251406

AF XY:

0.0710

show subpopulations

Gnomad AFR exome

AF:

0.0979

Gnomad AMR exome

AF:

0.114

Gnomad ASJ exome

AF:

0.0322

Gnomad EAS exome

AF:

0.122

Gnomad FIN exome

AF:

0.0431

Gnomad NFE exome

AF:

0.0481

Gnomad OTH exome

AF:

0.0569

GnomAD4 exome

AF:

0.0559

AC:

81567

AN:

1460436

Hom.:

2862

Cov.:

AF XY:

0.0570

AC XY:

41427

AN XY:

726602

show subpopulations

African (AFR)

AF:

0.0961

AC:

3215

AN:

33444

American (AMR)

AF:

0.110

AC:

4933

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0321

AC:

838

AN:

26134

East Asian (EAS)

AF:

0.139

AC:

5527

AN:

39688

South Asian (SAS)

AF:

0.106

AC:

9126

AN:

86212

European-Finnish (FIN)

AF:

0.0440

AC:

2352

AN:

53412

Middle Eastern (MID)

AF:

0.0385

AC:

220

AN:

5712

European-Non Finnish (NFE)

AF:

0.0466

AC:

51791

AN:

1110774

Other (OTH)

AF:

0.0591

AC:

3565

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

3658

7315

10973

14630

18288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2104

4208

6312

8416

10520

<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:

0.0684

AC:

10411

AN:

152240

Hom.:

437

Cov.:

AF XY:

0.0698

AC XY:

5198

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0958

AC:

3977

AN:

41516

American (AMR)

AF:

0.0887

AC:

1357

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0326

AC:

113

AN:

3470

East Asian (EAS)

AF:

0.126

AC:

652

AN:

5178

South Asian (SAS)

AF:

0.117

AC:

563

AN:

4830

European-Finnish (FIN)

AF:

0.0441

AC:

468

AN:

10612

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0452

AC:

3073

AN:

68018

Other (OTH)

AF:

0.0663

AC:

140

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

485

969

1454

1938

2423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

240

360

480

600

<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:

0.0533

Hom.:

1103

Bravo

AF:

0.0726

TwinsUK

AF:

0.0477

AC:

177

ALSPAC

AF:

0.0509

AC:

196

ESP6500AA

AF:

0.0867

AC:

382

ESP6500EA

AF:

0.0469

AC:

403

ExAC

AF:

0.0720

AC:

8737

Asia WGS

AF:

0.113

AC:

393

AN:

3478

EpiCase

AF:

0.0460

EpiControl

AF:

0.0446

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.086

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.2

MutationAssessor

Benign

2.0

PhyloP100

9.3

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.81

REVEL

Benign

0.11

Sift

Benign

0.31

Sift4G

Benign

0.082

Polyphen

0.96

Vest4

0.15

MPC

0.70

ClinPred

0.031

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.46

gMVP

0.69

Mutation Taster

=55/45

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over