rs3824968

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003105.6(SORL1):c.4752T>A(p.Ala1584=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 1,612,564 control chromosomes in the GnomAD database, including 95,938 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 8106 hom., cov: 32)

Exomes 𝑓: 0.34 ( 87832 hom. )

Consequence

SORL1
NM_003105.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.284

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 11-121605213-T-A is Benign according to our data. Variant chr11-121605213-T-A is described in ClinVar as [Benign]. Clinvar id is 1209934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-121605213-T-A is described in Lovd as [Likely_benign]. Variant chr11-121605213-T-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.284 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORL1	NM_003105.6 linkuse as main transcript	c.4752T>A	p.Ala1584=	synonymous_variant	34/48	ENST00000260197.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORL1	ENST00000260197.12 linkuse as main transcript	c.4752T>A	p.Ala1584=	synonymous_variant	34/48	1	NM_003105.6	P1

Frequencies

GnomAD3 genomes

AF:

0.302

AC:

45901

AN:

151984

Hom.:

8086

Cov.:

show subpopulations

Gnomad AFR

AF:

0.148

Gnomad AMI

AF:

0.277

Gnomad AMR

AF:

0.442

Gnomad ASJ

AF:

0.243

Gnomad EAS

AF:

0.591

Gnomad SAS

AF:

0.556

Gnomad FIN

AF:

0.389

Gnomad MID

AF:

0.307

Gnomad NFE

AF:

0.314

Gnomad OTH

AF:

0.309

GnomAD3 exomes

AF:

0.389

AC:

97703

AN:

250848

Hom.:

21511

AF XY:

0.394

AC XY:

53368

AN XY:

135568

show subpopulations

Gnomad AFR exome

AF:

0.142

Gnomad AMR exome

AF:

0.552

Gnomad ASJ exome

AF:

0.245

Gnomad EAS exome

AF:

0.611

Gnomad SAS exome

AF:

0.549

Gnomad FIN exome

AF:

0.376

Gnomad NFE exome

AF:

0.314

Gnomad OTH exome

AF:

0.354

GnomAD4 exome

AF:

0.336

AC:

490019

AN:

1460462

Hom.:

87832

Cov.:

AF XY:

0.342

AC XY:

248370

AN XY:

726598

show subpopulations

Gnomad4 AFR exome

AF:

0.137

Gnomad4 AMR exome

AF:

0.535

Gnomad4 ASJ exome

AF:

0.244

Gnomad4 EAS exome

AF:

0.539

Gnomad4 SAS exome

AF:

0.544

Gnomad4 FIN exome

AF:

0.379

Gnomad4 NFE exome

AF:

0.310

Gnomad4 OTH exome

AF:

0.340

GnomAD4 genome

AF:

0.302

AC:

45964

AN:

152102

Hom.:

8106

Cov.:

AF XY:

0.314

AC XY:

23336

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.149

Gnomad4 AMR

AF:

0.442

Gnomad4 ASJ

AF:

0.243

Gnomad4 EAS

AF:

0.590

Gnomad4 SAS

AF:

0.555

Gnomad4 FIN

AF:

0.389

Gnomad4 NFE

AF:

0.314

Gnomad4 OTH

AF:

0.317

Alfa

AF:

0.302

Hom.:

2334

Bravo

AF:

0.297

Asia WGS

AF:

0.536

AC:

1865

AN:

3478

EpiCase

AF:

0.307

EpiControl

AF:

0.311

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

SORL1-related condition

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

Cadd

Benign

7.7

Dann

Benign

0.65

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over