11-121500007-C-T

Variant names:

• chr11-121500007-C-T
• rs753780
• NM_003105.6:c.939+2958C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000260197.12(SORL1):​c.939+2958C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 152,216 control chromosomes in the GnomAD database, including 1,500 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.12 (1500 hom., cov: 33)
• Consequence: SORL1 ENST00000260197.12 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0570
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000260197.12. 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.939+2958C>T		intron	N/A	NP_003096.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	ENST00000260197.12	TSL:1 MANE Select	c.939+2958C>T		intron	N/A	ENSP00000260197.6
	SORL1	ENST00000532451.1	TSL:1	n.891+2958C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19009 AN: 152098 Hom.: 1496 Cov.: 33

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.0835

Gnomad AMR AF: 0.0976

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.0920

Gnomad FIN AF: 0.0350

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.132

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.125 AC: 19024 AN: 152216 Hom.: 1500 Cov.: 33 AF XY: 0.121 AC XY: 9003 AN XY: 74426

African (AFR) AF: 0.211 AC: 8735 AN: 41492

American (AMR) AF: 0.0974 AC: 1490 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 444 AN: 3472

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5188

South Asian (SAS) AF: 0.0925 AC: 446 AN: 4824

European-Finnish (FIN) AF: 0.0350 AC: 371 AN: 10606

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7132 AN: 68022

Other (OTH) AF: 0.131 AC: 276 AN: 2114

Alfa AF: 0.117 Hom.: 398

Bravo AF: 0.135

Asia WGS AF: 0.0570 AC: 199 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.1
DANN	Benign	0.75
PhyloP100		-0.057
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs753780; hg19: chr11-121370716;