Genetic Variant SORL1:c.5239+73C>T (chr11-121608249-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003105.6(SORL1):c.5239+73C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,222,666 control chromosomes in the GnomAD database, including 64,750 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 0.28 ( 7055 hom., cov: 32)

Exomes 𝑓: 0.31 ( 57695 hom. )

Consequence

SORL1
NM_003105.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.65

Publications

47 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003105.6. 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
	SORL1	NM_003105.6	MANE Select	c.5239+73C>T		intron	N/A	NP_003096.2	Q92673

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SORL1	ENST00000260197.12	TSL:1 MANE Select	c.5239+73C>T	intron	N/A	ENSP00000260197.6	Q92673
SORL1	ENST00000905166.1		c.5239+73C>T	intron	N/A	ENSP00000575225.1
SORL1	ENST00000905167.1		c.5122+73C>T	intron	N/A	ENSP00000575226.1

Frequencies

GnomAD3 genomes

AF:

0.276

AC:

41870

AN:

151898

Hom.:

7038

Cov.:

show subpopulations

Gnomad AFR

AF:

0.112

Gnomad AMI

AF:

0.188

Gnomad AMR

AF:

0.414

Gnomad ASJ

AF:

0.207

Gnomad EAS

AF:

0.585

Gnomad SAS

AF:

0.502

Gnomad FIN

AF:

0.389

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.292

Gnomad OTH

AF:

0.278

GnomAD4 exome

AF:

0.314

AC:

336584

AN:

1070650

Hom.:

57695

Cov.:

AF XY:

0.321

AC XY:

175087

AN XY:

546038

show subpopulations

African (AFR)

AF:

0.102

AC:

2495

AN:

24458

American (AMR)

AF:

0.503

AC:

17841

AN:

35482

Ashkenazi Jewish (ASJ)

AF:

0.207

AC:

4643

AN:

22422

East Asian (EAS)

AF:

0.531

AC:

19402

AN:

36564

South Asian (SAS)

AF:

0.491

AC:

35572

AN:

72508

European-Finnish (FIN)

AF:

0.378

AC:

19068

AN:

50430

Middle Eastern (MID)

AF:

0.299

AC:

1474

AN:

4936

European-Non Finnish (NFE)

AF:

0.285

AC:

221651

AN:

776952

Other (OTH)

AF:

0.308

AC:

14438

AN:

46898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

10900

21801

32701

43602

54502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6406

12812

19218

25624

32030

<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:

0.276

AC:

41909

AN:

152016

Hom.:

7055

Cov.:

AF XY:

0.288

AC XY:

21389

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.112

AC:

4642

AN:

41454

American (AMR)

AF:

0.415

AC:

6342

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.207

AC:

719

AN:

3468

East Asian (EAS)

AF:

0.584

AC:

3017

AN:

5170

South Asian (SAS)

AF:

0.501

AC:

2418

AN:

4828

European-Finnish (FIN)

AF:

0.389

AC:

4099

AN:

10526

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.292

AC:

19816

AN:

67970

Other (OTH)

AF:

0.286

AC:

603

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1479

2958

4437

5916

7395

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

444

888

1332

1776

2220

<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:

0.285

Hom.:

1494

Bravo

AF:

0.268

Asia WGS

AF:

0.514

AC:

1787

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.23

(source)

DANN

Benign

0.62

PhyloP100

-1.6

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over