Genetic Variant SORL1:c.5240-378C>T (chr11-121610698-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.5240-378C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 166,250 control chromosomes in the GnomAD database, including 8,746 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 0.30 ( 7894 hom., cov: 32)

Exomes 𝑓: 0.33 ( 852 hom. )

Consequence

SORL1
NM_003105.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.30

Publications

13 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:

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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=-1.03).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6 link	c.5240-378C>T		intron_variant	Intron 38 of 47	ENST00000260197.12	NP_003096.2	Q92673A0A024R3H2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12 link	c.5240-378C>T		intron_variant	Intron 38 of 47	1	NM_003105.6	ENSP00000260197.6		Q92673

Frequencies

GnomAD3 genomes

AF:

0.298

AC:

45266

AN:

151862

Hom.:

7874

Cov.:

show subpopulations

Gnomad AFR

AF:

0.145

Gnomad AMI

AF:

0.277

Gnomad AMR

AF:

0.437

Gnomad ASJ

AF:

0.241

Gnomad EAS

AF:

0.586

Gnomad SAS

AF:

0.548

Gnomad FIN

AF:

0.386

Gnomad MID

AF:

0.306

Gnomad NFE

AF:

0.310

Gnomad OTH

AF:

0.302

GnomAD4 exome

AF:

0.335

AC:

4777

AN:

14268

Hom.:

852

Cov.:

AF XY:

0.337

AC XY:

2507

AN XY:

7434

show subpopulations

African (AFR)

AF:

0.151

AC:

AN:

418

American (AMR)

AF:

0.488

AC:

400

AN:

820

Ashkenazi Jewish (ASJ)

AF:

0.224

AC:

104

AN:

464

East Asian (EAS)

AF:

0.545

AC:

377

AN:

692

South Asian (SAS)

AF:

0.503

AC:

366

AN:

728

European-Finnish (FIN)

AF:

0.351

AC:

244

AN:

696

Middle Eastern (MID)

AF:

0.360

AC:

AN:

European-Non Finnish (NFE)

AF:

0.305

AC:

2911

AN:

9542

Other (OTH)

AF:

0.343

AC:

294

AN:

858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

152

304

456

608

760

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.298

AC:

45330

AN:

151982

Hom.:

7894

Cov.:

AF XY:

0.310

AC XY:

23021

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.146

AC:

6044

AN:

41442

American (AMR)

AF:

0.438

AC:

6689

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.241

AC:

837

AN:

3472

East Asian (EAS)

AF:

0.585

AC:

3024

AN:

5166

South Asian (SAS)

AF:

0.546

AC:

2631

AN:

4816

European-Finnish (FIN)

AF:

0.386

AC:

4066

AN:

10534

Middle Eastern (MID)

AF:

0.316

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.310

AC:

21042

AN:

67956

Other (OTH)

AF:

0.309

AC:

651

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1550

3101

4651

6202

7752

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.305

Hom.:

20159

Bravo

AF:

0.293

Asia WGS

AF:

0.529

AC:

1840

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.014

(source)

DANN

Benign

0.69

PhyloP100

-3.3

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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11-121610698-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over