chr11-121605213-T-A

Variant names:

• chr11-121605213-T-A
• rs3824968
• NM_003105.6:c.4752T>A
• SORL1 p.Ala1584Ala

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003105.6(SORL1):​c.4752T>A​(p.Ala1584Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 1,612,564 control chromosomes in the GnomAD database, including 95,938 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8106 hom., cov: 32)
  • Exomes 𝑓: 0.34 (87832 hom.)
• Consequence: SORL1 NM_003105.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.284
• Publications: 64 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 11-121605213-T-A is Benign according to our data. Variant chr11-121605213-T-A is described in ClinVar as Benign. ClinVar VariationId is 1209934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.284 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.573 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	NM_003105.6	MANE Select	c.4752T>A	p.Ala1584Ala	synonymous	Exon 34 of 48	NP_003096.2	Q92673

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	ENST00000260197.12	TSL:1 MANE Select	c.4752T>A	p.Ala1584Ala	synonymous	Exon 34 of 48	ENSP00000260197.6	Q92673
	SORL1	ENST00000905166.1		c.4752T>A	p.Ala1584Ala	synonymous	Exon 34 of 48	ENSP00000575225.1
	SORL1	ENST00000905167.1		c.4635T>A	p.Ala1545Ala	synonymous	Exon 33 of 47	ENSP00000575226.1

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45901 AN: 151984 Hom.: 8086 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.442

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.591

Gnomad SAS AF: 0.556

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.309

GnomAD2 exomes AF: 0.389 AC: 97703 AN: 250848 AF XY: 0.394

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.552

Gnomad ASJ exome AF: 0.245

Gnomad EAS exome AF: 0.611

Gnomad FIN exome AF: 0.376

Gnomad NFE exome AF: 0.314

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.336 AC: 490019 AN: 1460462 Hom.: 87832 Cov.: 35 AF XY: 0.342 AC XY: 248370 AN XY: 726598

African (AFR) AF: 0.137 AC: 4595 AN: 33440

American (AMR) AF: 0.535 AC: 23849 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 6369 AN: 26100

East Asian (EAS) AF: 0.539 AC: 21404 AN: 39692

South Asian (SAS) AF: 0.544 AC: 46868 AN: 86118

European-Finnish (FIN) AF: 0.379 AC: 20209 AN: 53390

Middle Eastern (MID) AF: 0.370 AC: 2133 AN: 5764

European-Non Finnish (NFE) AF: 0.310 AC: 344089 AN: 1111016

Other (OTH) AF: 0.340 AC: 20503 AN: 60354

GnomAD4 genome AF: 0.302 AC: 45964 AN: 152102 Hom.: 8106 Cov.: 32 AF XY: 0.314 AC XY: 23336 AN XY: 74352

African (AFR) AF: 0.149 AC: 6176 AN: 41526

American (AMR) AF: 0.442 AC: 6760 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 843 AN: 3470

East Asian (EAS) AF: 0.590 AC: 3048 AN: 5166

South Asian (SAS) AF: 0.555 AC: 2673 AN: 4818

European-Finnish (FIN) AF: 0.389 AC: 4112 AN: 10576

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.314 AC: 21337 AN: 67954

Other (OTH) AF: 0.317 AC: 668 AN: 2108

Alfa AF: 0.302 Hom.: 2334

Bravo AF: 0.297

Asia WGS AF: 0.536 AC: 1865 AN: 3478

EpiCase AF: 0.307

EpiControl AF: 0.311

ClinVar

ClinVar submissions

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	-0.47
CADD	Benign	7.7
DANN	Benign	0.65
PhyloP100		0.28
Mutation Taster		=98/2	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3824968;

hg19: chr11-121475922;

COSMIC: COSV52749563;

COSMIC: COSV52749563;