11-121583440-C-G

Variant names:

• chr11-121583440-C-G
• rs73595277
• NM_003105.6:c.3581-18C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003105.6(SORL1):​c.3581-18C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.082 in 1,605,256 control chromosomes in the GnomAD database, including 7,753 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2199 hom., cov: 32)
  • Exomes 𝑓: 0.076 (5554 hom.)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.183
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-121583440-C-G is Benign according to our data. Variant chr11-121583440-C-G is described in ClinVar as Benign. ClinVar VariationId is 1209970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.29 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.3581-18C>G		intron	N/A	NP_003096.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	ENST00000260197.12	TSL:1 MANE Select	c.3581-18C>G		intron	N/A	ENSP00000260197.6
	SORL1	ENST00000905166.1		c.3581-18C>G		intron	N/A	ENSP00000575225.1
	SORL1	ENST00000905167.1		c.3464-18C>G		intron	N/A	ENSP00000575226.1

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20555 AN: 152058 Hom.: 2196 Cov.: 32

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.0937

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0439

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0736

Gnomad OTH AF: 0.129

GnomAD2 exomes AF: 0.0802 AC: 19482 AN: 242812 AF XY: 0.0768

Gnomad AFR exome AF: 0.299

Gnomad AMR exome AF: 0.0558

Gnomad ASJ exome AF: 0.0558

Gnomad EAS exome AF: 0.000679

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.0731

Gnomad OTH exome AF: 0.0809

GnomAD4 exome AF: 0.0764 AC: 111070 AN: 1453080 Hom.: 5554 Cov.: 31 AF XY: 0.0753 AC XY: 54422 AN XY: 722556

African (AFR) AF: 0.307 AC: 10151 AN: 33032

American (AMR) AF: 0.0602 AC: 2630 AN: 43710

Ashkenazi Jewish (ASJ) AF: 0.0551 AC: 1415 AN: 25692

East Asian (EAS) AF: 0.000282 AC: 11 AN: 39066

South Asian (SAS) AF: 0.0507 AC: 4322 AN: 85220

European-Finnish (FIN) AF: 0.104 AC: 5545 AN: 53258

Middle Eastern (MID) AF: 0.0802 AC: 460 AN: 5736

European-Non Finnish (NFE) AF: 0.0738 AC: 81691 AN: 1107376

Other (OTH) AF: 0.0808 AC: 4845 AN: 59990

GnomAD4 genome AF: 0.135 AC: 20569 AN: 152176 Hom.: 2199 Cov.: 32 AF XY: 0.134 AC XY: 9965 AN XY: 74404

African (AFR) AF: 0.294 AC: 12199 AN: 41466

American (AMR) AF: 0.0934 AC: 1428 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0496 AC: 172 AN: 3468

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.0437 AC: 211 AN: 4830

European-Finnish (FIN) AF: 0.109 AC: 1156 AN: 10606

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0736 AC: 5004 AN: 68016

Other (OTH) AF: 0.127 AC: 268 AN: 2110

Alfa AF: 0.0589 Hom.: 96

Bravo AF: 0.142

Asia WGS AF: 0.0380 AC: 132 AN: 3478

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.6
DANN	Benign	0.31
PhyloP100		0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs73595277; hg19: chr11-121454149; COSMIC: COSV52765344;