rs641120

Variant names:

• chr11-121510256-G-A
• rs641120
• NM_003105.6:c.940-2747G>A

Variant summary

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

The NM_003105.6(SORL1):​c.940-2747G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 152,052 control chromosomes in the GnomAD database, including 12,107 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 0.39 (12107 hom., cov: 32)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.359
• Publications: 32 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.53 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.940-2747G>A		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.940-2747G>A		intron_variant	Intron 6 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000532451.1	n.892-2747G>A		intron_variant	Intron 6 of 14	1

Frequencies

GnomAD3 genomes AF: 0.389 AC: 59048 AN: 151936 Hom.: 12090 Cov.: 32

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.477

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.394

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

GnomAD4 genome AF: 0.389 AC: 59084 AN: 152052 Hom.: 12107 Cov.: 32 AF XY: 0.388 AC XY: 28835 AN XY: 74314

African (AFR) AF: 0.271 AC: 11248 AN: 41466

American (AMR) AF: 0.351 AC: 5372 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1169 AN: 3470

East Asian (EAS) AF: 0.547 AC: 2829 AN: 5170

South Asian (SAS) AF: 0.445 AC: 2145 AN: 4822

European-Finnish (FIN) AF: 0.477 AC: 5034 AN: 10554

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

European-Non Finnish (NFE) AF: 0.443 AC: 30089 AN: 67968

Other (OTH) AF: 0.400 AC: 845 AN: 2110

Alfa AF: 0.406 Hom.: 1585

Bravo AF: 0.377

Asia WGS AF: 0.498 AC: 1732 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.7
DANN	Benign	0.40
PhyloP100		0.36
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: rs641120; hg19: chr11-121380965; COSMIC: COSV107279191;