chr11-121505242-A-G

Variant names:

• chr11-121505242-A-G
• rs4598682
• NM_003105.6:c.940-7761A>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.940-7761A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0422 in 152,044 control chromosomes in the GnomAD database, including 363 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 0.042 (363 hom., cov: 32)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.495
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.940-7761A>G		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.940-7761A>G		intron_variant	Intron 6 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000532451.1	n.892-7761A>G		intron_variant	Intron 6 of 14	1

Frequencies

GnomAD3 genomes AF: 0.0421 AC: 6401 AN: 151924 Hom.: 364 Cov.: 32

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.0439

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.0379

Gnomad FIN AF: 0.0497

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.0435

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

GnomAD4 genome AF: 0.0422 AC: 6412 AN: 152044 Hom.: 363 Cov.: 32 AF XY: 0.0481 AC XY: 3577 AN XY: 74354

African (AFR) AF: 0.0174 AC: 725 AN: 41550

American (AMR) AF: 0.156 AC: 2378 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0439 AC: 152 AN: 3464

East Asian (EAS) AF: 0.192 AC: 993 AN: 5184

South Asian (SAS) AF: 0.0375 AC: 181 AN: 4830

European-Finnish (FIN) AF: 0.0497 AC: 520 AN: 10466

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0188 AC: 1279 AN: 67946

Other (OTH) AF: 0.0436 AC: 92 AN: 2112

Alfa AF: 0.0346 Hom.: 42

Bravo AF: 0.0480

Asia WGS AF: 0.107 AC: 368 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.5
DANN	Benign	0.72
PhyloP100		0.49
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: rs4598682; hg19: chr11-121375951;