NM_003105.6:c.939+405A>G

Variant names:

• chr11-121497454-A-G
• rs923892
• NM_003105.6:c.939+405A>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.939+405A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 151,966 control chromosomes in the GnomAD database, including 25,439 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 0.58 (25439 hom., cov: 32)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.547
• Publications: 3 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=-0.71).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.939+405A>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.939+405A>G		intron_variant	Intron 6 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000532451.1	n.891+405A>G		intron_variant	Intron 6 of 14	1

Frequencies

GnomAD3 genomes AF: 0.576 AC: 87524 AN: 151848 Hom.: 25414 Cov.: 32

Gnomad AFR AF: 0.606

Gnomad AMI AF: 0.721

Gnomad AMR AF: 0.635

Gnomad ASJ AF: 0.663

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.526

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.557

Gnomad OTH AF: 0.587

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

GnomAD4 genome AF: 0.576 AC: 87588 AN: 151966 Hom.: 25439 Cov.: 32 AF XY: 0.579 AC XY: 42968 AN XY: 74262

African (AFR) AF: 0.606 AC: 25120 AN: 41442

American (AMR) AF: 0.635 AC: 9698 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.663 AC: 2299 AN: 3466

East Asian (EAS) AF: 0.451 AC: 2329 AN: 5162

South Asian (SAS) AF: 0.555 AC: 2671 AN: 4812

European-Finnish (FIN) AF: 0.526 AC: 5542 AN: 10542

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.557 AC: 37852 AN: 67952

Other (OTH) AF: 0.581 AC: 1225 AN: 2110

Alfa AF: 0.576 Hom.: 32170

Bravo AF: 0.583

Asia WGS AF: 0.490 AC: 1704 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	10
DANN	Benign	0.82
PhyloP100		0.55
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: rs923892; hg19: chr11-121368163;