11-121497212-C-T

Variant names:

• chr11-121497212-C-T
• rs668387
• NM_003105.6:c.939+163C>T

Variant summary

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

The NM_003105.6(SORL1):​c.939+163C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 152,000 control chromosomes in the GnomAD database, including 12,551 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 0.40 (12551 hom., cov: 32)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0990
• Publications: 40 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=-0.66).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.939+163C>T		intron_variant	Intron 6 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.939+163C>T		intron_variant	Intron 6 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000532451.1	n.891+163C>T		intron_variant	Intron 6 of 14	1

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60661 AN: 151882 Hom.: 12533 Cov.: 32

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.476

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.400

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

GnomAD4 genome AF: 0.399 AC: 60708 AN: 152000 Hom.: 12551 Cov.: 32 AF XY: 0.399 AC XY: 29620 AN XY: 74262

African (AFR) AF: 0.309 AC: 12798 AN: 41436

American (AMR) AF: 0.357 AC: 5452 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1170 AN: 3472

East Asian (EAS) AF: 0.549 AC: 2839 AN: 5170

South Asian (SAS) AF: 0.445 AC: 2141 AN: 4816

European-Finnish (FIN) AF: 0.476 AC: 5010 AN: 10532

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.443 AC: 30087 AN: 67982

Other (OTH) AF: 0.406 AC: 858 AN: 2112

Alfa AF: 0.321 Hom.: 1314

Bravo AF: 0.389

Asia WGS AF: 0.499 AC: 1735 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.7
DANN	Benign	0.78
PhyloP100		-0.099
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: rs668387; hg19: chr11-121367921; COSMIC: COSV52750637;