11-121586253-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003105.6(SORL1):c.3738C>T(p.Asn1246=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.07

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]

ACMG classification

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/exons	MANE	UniProt
SORL1	NM_003105.6	c.3738C>T	p.Asn1246=	synonymous_variant	27/48	ENST00000260197.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORL1	ENST00000260197.12	c.3738C>T	p.Asn1246=	synonymous_variant	27/48	1	NM_003105.6	P1
SORL1	ENST00000525532.5	c.570C>T	p.Asn190=	synonymous_variant	7/28	2
SORL1	ENST00000534286.5	c.468C>T	p.Asn156=	synonymous_variant	4/25	2
SORL1	ENST00000532694.5	c.276C>T	p.Asn92=	synonymous_variant	4/25	2

Frequencies

GnomAD3 genomes AF: 0.565 AC: 85871 AN: 151962 Hom.: 25542 Cov.: 32

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

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.: 38 AF XY: 0.613 AC XY: 445362 AN XY: 726266

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.: 32 AF XY: 0.555 AC XY: 41242 AN XY: 74342

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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

SORL1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 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	-0.43
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

Other links and lift over

dbSNP: rs1699102; hg19: chr11-121456962; COSMIC: COSV52755241; COSMIC: COSV52755241;