NM_003105.6:c.285+4534G>A

Variant names:

• chr11-121457150-G-A
• rs582446
• NM_003105.6:c.285+4534G>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.285+4534G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.761 in 152,012 control chromosomes in the GnomAD database, including 45,630 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 0.76 (45630 hom., cov: 31)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.985
• Publications: 6 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.285+4534G>A		intron_variant	Intron 1 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.285+4534G>A		intron_variant	Intron 1 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000532451.1	n.237+4534G>A		intron_variant	Intron 1 of 14	1

Frequencies

GnomAD3 genomes AF: 0.761 AC: 115640 AN: 151894 Hom.: 45623 Cov.: 31

Gnomad AFR AF: 0.529

Gnomad AMI AF: 0.856

Gnomad AMR AF: 0.799

Gnomad ASJ AF: 0.909

Gnomad EAS AF: 0.868

Gnomad SAS AF: 0.873

Gnomad FIN AF: 0.814

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.860

Gnomad OTH AF: 0.781

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

GnomAD4 genome AF: 0.761 AC: 115694 AN: 152012 Hom.: 45630 Cov.: 31 AF XY: 0.761 AC XY: 56535 AN XY: 74332

African (AFR) AF: 0.529 AC: 21874 AN: 41374

American (AMR) AF: 0.799 AC: 12212 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.909 AC: 3157 AN: 3472

East Asian (EAS) AF: 0.867 AC: 4495 AN: 5182

South Asian (SAS) AF: 0.872 AC: 4199 AN: 4814

European-Finnish (FIN) AF: 0.814 AC: 8606 AN: 10572

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.860 AC: 58475 AN: 68010

Other (OTH) AF: 0.783 AC: 1649 AN: 2106

Alfa AF: 0.808 Hom.: 18853

Bravo AF: 0.748

Asia WGS AF: 0.838 AC: 2914 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.39
DANN	Benign	0.68
PhyloP100		-0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs582446; hg19: chr11-121327859;