chr11-121570811-A-G

Variant names:

• chr11-121570811-A-G
• rs1792124
• NM_003105.6:c.3337+541A>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.3337+541A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.95 in 152,284 control chromosomes in the GnomAD database, including 68,994 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 0.95 (68994 hom., cov: 33)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.439
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.3337+541A>G		intron_variant	Intron 23 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.3337+541A>G		intron_variant	Intron 23 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000525532.5	c.169+541A>G		intron_variant	Intron 3 of 27	2		ENSP00000434634.1

Frequencies

GnomAD3 genomes AF: 0.951 AC: 144642 AN: 152166 Hom.: 68955 Cov.: 33

Gnomad AFR AF: 0.875

Gnomad AMI AF: 0.995

Gnomad AMR AF: 0.972

Gnomad ASJ AF: 0.988

Gnomad EAS AF: 0.926

Gnomad SAS AF: 0.978

Gnomad FIN AF: 0.992

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.982

Gnomad OTH AF: 0.964

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

GnomAD4 genome AF: 0.950 AC: 144740 AN: 152284 Hom.: 68994 Cov.: 33 AF XY: 0.953 AC XY: 70932 AN XY: 74462

African (AFR) AF: 0.874 AC: 36309 AN: 41520

American (AMR) AF: 0.972 AC: 14869 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.988 AC: 3432 AN: 3472

East Asian (EAS) AF: 0.925 AC: 4799 AN: 5186

South Asian (SAS) AF: 0.978 AC: 4723 AN: 4828

European-Finnish (FIN) AF: 0.992 AC: 10538 AN: 10622

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.982 AC: 66834 AN: 68030

Other (OTH) AF: 0.965 AC: 2041 AN: 2116

Alfa AF: 0.963 Hom.: 32728

Bravo AF: 0.945

Asia WGS AF: 0.951 AC: 3304 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.1
DANN	Benign	0.82
PhyloP100		-0.44
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: rs1792124; hg19: chr11-121441520;