11-121470553-G-A

Variant names:

• chr11-121470553-G-A
• rs7945931
• NM_003105.6:c.402+430G>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.402+430G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 152,244 control chromosomes in the GnomAD database, including 1,314 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 0.12 (1314 hom., cov: 33)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.162
• Publications: 5 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.402+430G>A		intron_variant	Intron 2 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.402+430G>A		intron_variant	Intron 2 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000532451.1	n.354+430G>A		intron_variant	Intron 2 of 14	1

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18240 AN: 152126 Hom.: 1313 Cov.: 33

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.0850

Gnomad ASJ AF: 0.0904

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.0667

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0889

Gnomad OTH AF: 0.121

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

GnomAD4 genome AF: 0.120 AC: 18252 AN: 152244 Hom.: 1314 Cov.: 33 AF XY: 0.117 AC XY: 8699 AN XY: 74440

African (AFR) AF: 0.198 AC: 8240 AN: 41530

American (AMR) AF: 0.0849 AC: 1299 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0904 AC: 314 AN: 3472

East Asian (EAS) AF: 0.126 AC: 651 AN: 5176

South Asian (SAS) AF: 0.131 AC: 632 AN: 4830

European-Finnish (FIN) AF: 0.0667 AC: 707 AN: 10598

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0889 AC: 6045 AN: 68022

Other (OTH) AF: 0.119 AC: 252 AN: 2116

Alfa AF: 0.0997 Hom.: 2697

Bravo AF: 0.127

Asia WGS AF: 0.124 AC: 432 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.76
DANN	Benign	0.49
PhyloP100		0.16
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: rs7945931; hg19: chr11-121341262;