NM_003105.6:c.4176C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_003105.6(SORL1):c.4176C>T(p.Asn1392Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0273 in 1,614,016 control chromosomes in the GnomAD database, including 1,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.067 ( 767 hom., cov: 33)

Exomes 𝑓: 0.023 ( 1034 hom. )

Consequence

SORL1
NM_003105.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.37

Publications

28 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 11-121590137-C-T is Benign according to our data. Variant chr11-121590137-C-T is described in ClinVar as Benign. ClinVar VariationId is 1600983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.37 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6 link	c.4176C>T	p.Asn1392Asn	synonymous_variant	Exon 30 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.4176C>T	p.Asn1392Asn	synonymous_variant	Exon 30 of 48	1	NM_003105.6	ENSP00000260197.6	Q92673
SORL1	ENST00000525532.5 link	c.1008C>T	p.Asn336Asn	synonymous_variant	Exon 10 of 28	2		ENSP00000434634.1	E9PPB3
SORL1	ENST00000534286.5 link	c.906C>T	p.Asn302Asn	synonymous_variant	Exon 7 of 25	2		ENSP00000436447.1	E9PP43
SORL1	ENST00000532694.5 link	c.714C>T	p.Asn238Asn	synonymous_variant	Exon 7 of 25	2		ENSP00000432131.1	E9PS32

Frequencies

GnomAD3 genomes

AF:

0.0667

AC:

10146

AN:

152112

Hom.:

767

Cov.:

show subpopulations

Gnomad AFR

AF:

0.187

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0349

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.0645

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.00801

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0181

Gnomad OTH

AF:

0.0488

GnomAD2 exomes

AF:

0.0317

AC:

7984

AN:

251474

AF XY:

0.0284

show subpopulations

Gnomad AFR exome

AF:

0.195

Gnomad AMR exome

AF:

0.0162

Gnomad ASJ exome

AF:

0.0124

Gnomad EAS exome

AF:

0.0561

Gnomad FIN exome

AF:

0.00919

Gnomad NFE exome

AF:

0.0185

Gnomad OTH exome

AF:

0.0202

GnomAD4 exome

AF:

0.0232

AC:

33874

AN:

1461786

Hom.:

1034

Cov.:

AF XY:

0.0225

AC XY:

16387

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.195

AC:

6531

AN:

33460

American (AMR)

AF:

0.0177

AC:

790

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0122

AC:

318

AN:

26136

East Asian (EAS)

AF:

0.0790

AC:

3138

AN:

39698

South Asian (SAS)

AF:

0.0214

AC:

1850

AN:

86258

European-Finnish (FIN)

AF:

0.00867

AC:

463

AN:

53418

Middle Eastern (MID)

AF:

0.0265

AC:

153

AN:

5768

European-Non Finnish (NFE)

AF:

0.0170

AC:

18944

AN:

1111940

Other (OTH)

AF:

0.0279

AC:

1687

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

1699

3399

5098

6798

8497

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

832

1664

2496

3328

4160

<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:

0.0667

AC:

10157

AN:

152230

Hom.:

767

Cov.:

AF XY:

0.0646

AC XY:

4807

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.186

AC:

7732

AN:

41504

American (AMR)

AF:

0.0349

AC:

534

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3470

East Asian (EAS)

AF:

0.0649

AC:

336

AN:

5178

South Asian (SAS)

AF:

0.0178

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00801

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0181

AC:

1228

AN:

68018

Other (OTH)

AF:

0.0483

AC:

102

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

427

854

1282

1709

2136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<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:

0.0362

Hom.:

465

Bravo

AF:

0.0738

Asia WGS

AF:

0.0470

AC:

162

AN:

3478

EpiCase

AF:

0.0188

EpiControl

AF:

0.0205

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SORL1-related disorder

Benign:1

May 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

-0.45

CADD

Benign

6.1

(source)

DANN

Benign

0.85

PhyloP100

-1.4

PromoterAI

-0.044

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over