rs2070045

Positions:

• chr11-121577381-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003105.6(SORL1):​c.3561T>G​(p.Ser1187=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,609,520 control chromosomes in the GnomAD database, including 59,433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5264 hom., cov: 33)
  • Exomes 𝑓: 0.26 (54169 hom.)
• Consequence: SORL1 NM_003105.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.19

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 11-121577381-T-G is Benign according to our data. Variant chr11-121577381-T-G is described in ClinVar as [Benign]. Clinvar id is 1210021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-121577381-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.19 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SORL1	NM_003105.6	c.3561T>G	p.Ser1187=	synonymous_variant	25/48	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.3561T>G	p.Ser1187=	synonymous_variant	25/48	1	NM_003105.6	ENSP00000260197	P1
SORL1	ENST00000525532.5	c.393T>G	p.Ser131=	synonymous_variant	5/28	2		ENSP00000434634
SORL1	ENST00000534286.5	c.291T>G	p.Ser97=	synonymous_variant	2/25	2		ENSP00000436447
SORL1	ENST00000532694.5	c.99T>G	p.Ser33=	synonymous_variant	2/25	2		ENSP00000432131

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35590 AN: 152042 Hom.: 5241 Cov.: 33

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.565

Gnomad SAS AF: 0.468

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.246

GnomAD3 exomes AF: 0.321 AC: 79110 AN: 246584 Hom.: 15666 AF XY: 0.321 AC XY: 42743 AN XY: 133336

Gnomad AFR exome AF: 0.0994

Gnomad AMR exome AF: 0.529

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.582

Gnomad SAS exome AF: 0.457

Gnomad FIN exome AF: 0.251

Gnomad NFE exome AF: 0.235

Gnomad OTH exome AF: 0.284

GnomAD4 exome AF: 0.257 AC: 373866 AN: 1457360 Hom.: 54169 Cov.: 33 AF XY: 0.262 AC XY: 190010 AN XY: 724922

Gnomad4 AFR exome AF: 0.0942

Gnomad4 AMR exome AF: 0.505

Gnomad4 ASJ exome AF: 0.212

Gnomad4 EAS exome AF: 0.516

Gnomad4 SAS exome AF: 0.450

Gnomad4 FIN exome AF: 0.254

Gnomad4 NFE exome AF: 0.228

Gnomad4 OTH exome AF: 0.268

GnomAD4 genome AF: 0.234 AC: 35630 AN: 152160 Hom.: 5264 Cov.: 33 AF XY: 0.245 AC XY: 18191 AN XY: 74368

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.394

Gnomad4 ASJ AF: 0.208

Gnomad4 EAS AF: 0.564

Gnomad4 SAS AF: 0.467

Gnomad4 FIN AF: 0.261

Gnomad4 NFE AF: 0.234

Gnomad4 OTH AF: 0.256

Alfa AF: 0.236 Hom.: 7502

Bravo AF: 0.236

Asia WGS AF: 0.505 AC: 1755 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

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	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

SORL1-related disorder Benign:1

Benign, no assertion criteria provided

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.0
DANN	Benign	0.72

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: rs2070045; hg19: chr11-121448090; COSMIC: COSV52749539;