11-121564878-T-C

Variant names:

• chr11-121564878-T-C
• rs11218343
• NM_003105.6:c.3050-2062T>C

Variant summary

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

The NM_003105.6(SORL1):​c.3050-2062T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0629 in 152,222 control chromosomes in the GnomAD database, including 467 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 0.063 (467 hom., cov: 32)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0730
• Publications: 172 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.3050-2062T>C		intron_variant	Intron 21 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.3050-2062T>C		intron_variant	Intron 21 of 47	1	NM_003105.6	ENSP00000260197.6

Frequencies

GnomAD3 genomes AF: 0.0629 AC: 9561 AN: 152106 Hom.: 468 Cov.: 32

Gnomad AFR AF: 0.0801

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0688

Gnomad ASJ AF: 0.0640

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.0734

Gnomad FIN AF: 0.0249

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0390

Gnomad OTH AF: 0.0559

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

GnomAD4 genome AF: 0.0629 AC: 9570 AN: 152222 Hom.: 467 Cov.: 32 AF XY: 0.0637 AC XY: 4744 AN XY: 74434

African (AFR) AF: 0.0803 AC: 3332 AN: 41518

American (AMR) AF: 0.0688 AC: 1052 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0640 AC: 222 AN: 3470

East Asian (EAS) AF: 0.299 AC: 1551 AN: 5180

South Asian (SAS) AF: 0.0725 AC: 350 AN: 4830

European-Finnish (FIN) AF: 0.0249 AC: 264 AN: 10606

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0390 AC: 2653 AN: 68010

Other (OTH) AF: 0.0553 AC: 117 AN: 2114

Alfa AF: 0.0554 Hom.: 726

Bravo AF: 0.0687

Asia WGS AF: 0.165 AC: 573 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.8
DANN	Benign	0.44
PhyloP100		-0.073
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: rs11218343; hg19: chr11-121435587;