11-121577381-T-G

Variant names:

• chr11-121577381-T-G
• rs2070045
• NM_003105.6:c.3561T>G

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.3561T>G​(p.Ser1187Ser) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S1187S) has been classified as Uncertain significance.

• 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
• Publications: 75 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=-0.59).
• BP6: Variant 11-121577381-T-G is Benign according to our data. Variant chr11-121577381-T-G is described in ClinVar as Benign. ClinVar VariationId is 1210021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.3561T>G	p.Ser1187Ser	synonymous	Exon 25 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.3561T>G	p.Ser1187Ser	synonymous	Exon 25 of 48	ENSP00000260197.6	Q92673
	SORL1	ENST00000905166.1		c.3561T>G	p.Ser1187Ser	synonymous	Exon 25 of 48	ENSP00000575225.1
	SORL1	ENST00000905167.1		c.3444T>G	p.Ser1148Ser	synonymous	Exon 24 of 47	ENSP00000575226.1

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

GnomAD2 exomes AF: 0.321 AC: 79110 AN: 246584 AF XY: 0.321

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 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

African (AFR) AF: 0.0942 AC: 3132 AN: 33266

American (AMR) AF: 0.505 AC: 22148 AN: 43818

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 5476 AN: 25852

East Asian (EAS) AF: 0.516 AC: 20455 AN: 39664

South Asian (SAS) AF: 0.450 AC: 38514 AN: 85618

European-Finnish (FIN) AF: 0.254 AC: 13546 AN: 53304

Middle Eastern (MID) AF: 0.266 AC: 1528 AN: 5746

European-Non Finnish (NFE) AF: 0.228 AC: 252930 AN: 1109870

Other (OTH) AF: 0.268 AC: 16137 AN: 60222

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

African (AFR) AF: 0.103 AC: 4287 AN: 41554

American (AMR) AF: 0.394 AC: 6014 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 720 AN: 3468

East Asian (EAS) AF: 0.564 AC: 2913 AN: 5164

South Asian (SAS) AF: 0.467 AC: 2248 AN: 4818

European-Finnish (FIN) AF: 0.261 AC: 2764 AN: 10582

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15913 AN: 67980

Other (OTH) AF: 0.256 AC: 539 AN: 2108

Alfa AF: 0.235 Hom.: 9103

Bravo AF: 0.236

Asia WGS AF: 0.505 AC: 1755 AN: 3478

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	-0.59
CADD	Benign	4.0
DANN	Benign	0.72
PhyloP100		-1.2
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: rs2070045; hg19: chr11-121448090; COSMIC: COSV52749539;