dbSNP rs6589885: SORL1:c.2571+15G>A (chr11-121555333-G-A) – ACMG Classification: Benign (-20 pts)

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.2571+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,612,496 control chromosomes in the GnomAD database, including 547 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 103 hom., cov: 33)

Exomes 𝑓: 0.020 ( 444 hom. )

Consequence

SORL1
NM_003105.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -5.46

Publications

8 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 (BayesDel_noAF=-0.89).

BP6

Variant 11-121555333-G-A is Benign according to our data. Variant chr11-121555333-G-A is described in ClinVar as Benign. ClinVar VariationId is 1548278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0836 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.2571+15G>A		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.2571+15G>A	intron	N/A	ENSP00000260197.6	Q92673
SORL1	ENST00000905166.1		c.2571+15G>A	intron	N/A	ENSP00000575225.1
SORL1	ENST00000905167.1		c.2454+15G>A	intron	N/A	ENSP00000575226.1

Frequencies

GnomAD3 genomes

AF:

0.0304

AC:

4627

AN:

152136

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0571

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0216

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.0899

Gnomad SAS

AF:

0.0215

Gnomad FIN

AF:

0.00792

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0174

Gnomad OTH

AF:

0.0215

GnomAD2 exomes

AF:

0.0246

AC:

6153

AN:

250560

AF XY:

0.0236

show subpopulations

Gnomad AFR exome

AF:

0.0591

Gnomad AMR exome

AF:

0.00975

Gnomad ASJ exome

AF:

0.0123

Gnomad EAS exome

AF:

0.0949

Gnomad FIN exome

AF:

0.00865

Gnomad NFE exome

AF:

0.0179

Gnomad OTH exome

AF:

0.0168

GnomAD4 exome

AF:

0.0196

AC:

28554

AN:

1460242

Hom.:

444

Cov.:

AF XY:

0.0195

AC XY:

14179

AN XY:

726438

show subpopulations

African (AFR)

AF:

0.0602

AC:

2012

AN:

33404

American (AMR)

AF:

0.0105

AC:

467

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.0120

AC:

314

AN:

26094

East Asian (EAS)

AF:

0.0942

AC:

3730

AN:

39612

South Asian (SAS)

AF:

0.0214

AC:

1846

AN:

86150

European-Finnish (FIN)

AF:

0.00816

AC:

435

AN:

53298

Middle Eastern (MID)

AF:

0.0203

AC:

117

AN:

5758

European-Non Finnish (NFE)

AF:

0.0166

AC:

18400

AN:

1110966

Other (OTH)

AF:

0.0205

AC:

1233

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1284

2568

3851

5135

6419

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

766

1532

2298

3064

3830

<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:

0.0304

AC:

4632

AN:

152254

Hom.:

103

Cov.:

AF XY:

0.0297

AC XY:

2209

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0570

AC:

2367

AN:

41536

American (AMR)

AF:

0.0216

AC:

330

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3472

East Asian (EAS)

AF:

0.0903

AC:

468

AN:

5180

South Asian (SAS)

AF:

0.0215

AC:

104

AN:

4828

European-Finnish (FIN)

AF:

0.00792

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0174

AC:

1183

AN:

68012

Other (OTH)

AF:

0.0213

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

230

459

689

918

1148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0269

Hom.:

Bravo

AF:

0.0329

Asia WGS

AF:

0.0520

AC:

182

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.0090

(source)

DANN

Benign

0.62

PhyloP100

-5.5

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