11-121586253-C-T

Variant names:

• chr11-121586253-C-T
• rs1699102
• NM_003105.6:c.3738C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.07
• Publications: 57 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1209963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003105.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	NM_003105.6	MANE Select	c.3738C>T	p.Asn1246Asn	synonymous	Exon 27 of 48	NP_003096.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	ENST00000260197.12	TSL:1 MANE Select	c.3738C>T	p.Asn1246Asn	synonymous	Exon 27 of 48	ENSP00000260197.6
	SORL1	ENST00000905166.1		c.3738C>T	p.Asn1246Asn	synonymous	Exon 27 of 48	ENSP00000575225.1
	SORL1	ENST00000905167.1		c.3621C>T	p.Asn1207Asn	synonymous	Exon 26 of 47	ENSP00000575226.1

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

GnomAD2 exomes AF: 0.527 AC: 132555 AN: 251466 AF XY: 0.532

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 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

African (AFR) AF: 0.488 AC: 16304 AN: 33440

American (AMR) AF: 0.350 AC: 15667 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.717 AC: 18726 AN: 26122

East Asian (EAS) AF: 0.157 AC: 6212 AN: 39690

South Asian (SAS) AF: 0.381 AC: 32851 AN: 86212

European-Finnish (FIN) AF: 0.633 AC: 33797 AN: 53408

Middle Eastern (MID) AF: 0.579 AC: 3319 AN: 5736

European-Non Finnish (NFE) AF: 0.668 AC: 741142 AN: 1110088

Other (OTH) AF: 0.591 AC: 35648 AN: 60326

GnomAD4 genome AF: 0.565 AC: 85900 AN: 152080 Hom.: 25541 Cov.: 32 AF XY: 0.555 AC XY: 41242 AN XY: 74342

African (AFR) AF: 0.496 AC: 20569 AN: 41458

American (AMR) AF: 0.446 AC: 6820 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.716 AC: 2484 AN: 3470

East Asian (EAS) AF: 0.127 AC: 658 AN: 5178

South Asian (SAS) AF: 0.362 AC: 1747 AN: 4822

European-Finnish (FIN) AF: 0.619 AC: 6552 AN: 10578

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.662 AC: 45022 AN: 67986

Other (OTH) AF: 0.580 AC: 1223 AN: 2110

Alfa AF: 0.624 Hom.: 48198

Bravo AF: 0.550

Asia WGS AF: 0.247 AC: 862 AN: 3478

EpiCase AF: 0.663

EpiControl AF: 0.662

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	SORL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.68
DANN	Benign	0.64
PhyloP100		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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