rs4935775

Variant names:

• chr11-121518793-T-G
• rs4935775
• NM_003105.6:c.1212-1864T>G

Variant summary

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

The NM_003105.6(SORL1):​c.1212-1864T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 151,958 control chromosomes in the GnomAD database, including 9,330 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 0.32 (9330 hom., cov: 31)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00700
• Publications: 9 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.1212-1864T>G		intron_variant	Intron 8 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.1212-1864T>G		intron_variant	Intron 8 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000532451.1	n.1164-1864T>G		intron_variant	Intron 8 of 14	1

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49312 AN: 151838 Hom.: 9332 Cov.: 31

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.502

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.334

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

GnomAD4 genome AF: 0.324 AC: 49296 AN: 151958 Hom.: 9330 Cov.: 31 AF XY: 0.324 AC XY: 24078 AN XY: 74260

African (AFR) AF: 0.147 AC: 6104 AN: 41454

American (AMR) AF: 0.294 AC: 4489 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.502 AC: 1742 AN: 3470

East Asian (EAS) AF: 0.118 AC: 613 AN: 5178

South Asian (SAS) AF: 0.317 AC: 1523 AN: 4806

European-Finnish (FIN) AF: 0.457 AC: 4805 AN: 10518

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.422 AC: 28656 AN: 67936

Other (OTH) AF: 0.330 AC: 698 AN: 2112

Alfa AF: 0.398 Hom.: 6487

Bravo AF: 0.302

Asia WGS AF: 0.203 AC: 707 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.0
DANN	Benign	0.68
PhyloP100		0.0070
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4935775; hg19: chr11-121389502;