11-121586253-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_003105.6(SORL1):c.3738C>T(p.Asn1246Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 1,611,814 control chromosomes in the GnomAD database, including 316,661 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.56 ( 25541 hom., cov: 32)

Exomes 𝑓: 0.62 ( 291120 hom. )

Consequence

SORL1
NM_003105.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.07

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 11-121586253-C-T is Benign according to our data. Variant chr11-121586253-C-T is described in ClinVar as [Benign]. Clinvar id is 1209963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-121586253-C-T is described in Lovd as [Likely_benign]. Variant chr11-121586253-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.07 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6 link	c.3738C>T	p.Asn1246Asn	synonymous_variant	Exon 27 of 48	ENST00000260197.12	NP_003096.2	Q92673A0A024R3H2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SORL1	ENST00000260197.12 link	c.3738C>T	p.Asn1246Asn	synonymous_variant	Exon 27 of 48	1	NM_003105.6	ENSP00000260197.6	Q92673
SORL1	ENST00000525532.5 link	c.570C>T	p.Asn190Asn	synonymous_variant	Exon 7 of 28	2		ENSP00000434634.1	E9PPB3
SORL1	ENST00000534286.5 link	c.468C>T	p.Asn156Asn	synonymous_variant	Exon 4 of 25	2		ENSP00000436447.1	E9PP43
SORL1	ENST00000532694.5 link	c.276C>T	p.Asn92Asn	synonymous_variant	Exon 4 of 25	2		ENSP00000432131.1	E9PS32

Frequencies

GnomAD3 genomes

AF:

0.565

AC:

85871

AN:

151962

Hom.:

25542

Cov.:

show subpopulations

Gnomad AFR

AF:

0.496

Gnomad AMI

AF:

0.715

Gnomad AMR

AF:

0.447

Gnomad ASJ

AF:

0.716

Gnomad EAS

AF:

0.126

Gnomad SAS

AF:

0.360

Gnomad FIN

AF:

0.619

Gnomad MID

AF:

0.611

Gnomad NFE

AF:

0.662

Gnomad OTH

AF:

0.586

GnomAD3 exomes

AF:

0.527

AC:

132555

AN:

251466

Hom.:

39225

AF XY:

0.532

AC XY:

72361

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.492

Gnomad AMR exome

AF:

0.330

Gnomad ASJ exome

AF:

0.713

Gnomad EAS exome

AF:

0.108

Gnomad SAS exome

AF:

0.378

Gnomad FIN exome

AF:

0.636

Gnomad NFE exome

AF:

0.660

Gnomad OTH exome

AF:

0.580

GnomAD4 exome

AF:

0.619

AC:

903666

AN:

1459734

Hom.:

291120

Cov.:

AF XY:

0.613

AC XY:

445362

AN XY:

726266

show subpopulations

Gnomad4 AFR exome

AF:

0.488

Gnomad4 AMR exome

AF:

0.350

Gnomad4 ASJ exome

AF:

0.717

Gnomad4 EAS exome

AF:

0.157

Gnomad4 SAS exome

AF:

0.381

Gnomad4 FIN exome

AF:

0.633

Gnomad4 NFE exome

AF:

0.668

Gnomad4 OTH exome

AF:

0.591

GnomAD4 genome

AF:

0.565

AC:

85900

AN:

152080

Hom.:

25541

Cov.:

AF XY:

0.555

AC XY:

41242

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.496

Gnomad4 AMR

AF:

0.446

Gnomad4 ASJ

AF:

0.716

Gnomad4 EAS

AF:

0.127

Gnomad4 SAS

AF:

0.362

Gnomad4 FIN

AF:

0.619

Gnomad4 NFE

AF:

0.662

Gnomad4 OTH

AF:

0.580

Alfa

AF:

0.630

Hom.:

38740

Bravo

AF:

0.550

Asia WGS

AF:

0.247

AC:

862

AN:

3478

EpiCase

AF:

0.663

EpiControl

AF:

0.662

ClinVar

Significance: Benign

Submissions summary: Benign:5

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

- -

SORL1-related disorder

Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.68

DANN

Benign

0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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