NM_003105.6:c.4369+2223G>A

Variant names:

• chr11-121593379-G-A
• rs10892759
• NM_003105.6:c.4369+2223G>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.4369+2223G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.47 in 152,104 control chromosomes in the GnomAD database, including 18,080 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 0.47 (18080 hom., cov: 33)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.92

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.64 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.4369+2223G>A		intron_variant	Intron 31 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.4369+2223G>A		intron_variant	Intron 31 of 47	1	NM_003105.6	ENSP00000260197.6

Frequencies

GnomAD3 genomes AF: 0.470 AC: 71389 AN: 151986 Hom.: 18038 Cov.: 33

Gnomad AFR AF: 0.628

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.547

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.659

Gnomad SAS AF: 0.616

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.454

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

GnomAD4 genome AF: 0.470 AC: 71493 AN: 152104 Hom.: 18080 Cov.: 33 AF XY: 0.477 AC XY: 35494 AN XY: 74354

African (AFR) AF: 0.628 AC: 26070 AN: 41502

American (AMR) AF: 0.548 AC: 8365 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 957 AN: 3470

East Asian (EAS) AF: 0.658 AC: 3411 AN: 5180

South Asian (SAS) AF: 0.614 AC: 2965 AN: 4826

European-Finnish (FIN) AF: 0.414 AC: 4380 AN: 10570

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.353 AC: 23987 AN: 67972

Other (OTH) AF: 0.459 AC: 968 AN: 2108

Alfa AF: 0.420 Hom.: 2460

Bravo AF: 0.485

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.060
DANN	Benign	0.61
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Other links and lift over

dbSNP: rs10892759; hg19: chr11-121464088;