rs985421

Variant names:

• chr11-121491607-G-A
• rs985421
• NM_003105.6:c.758+1497G>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.758+1497G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0325 in 152,222 control chromosomes in the GnomAD database, including 338 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 0.033 (338 hom., cov: 32)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56
• Publications: 11 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.758+1497G>A		intron_variant	Intron 5 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.758+1497G>A		intron_variant	Intron 5 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000532451.1	n.710+1497G>A		intron_variant	Intron 5 of 14	1

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4950 AN: 152102 Hom.: 339 Cov.: 32

Gnomad AFR AF: 0.00546

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.0335

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

GnomAD4 genome AF: 0.0325 AC: 4952 AN: 152222 Hom.: 338 Cov.: 32 AF XY: 0.0363 AC XY: 2702 AN XY: 74424

African (AFR) AF: 0.00542 AC: 225 AN: 41540

American (AMR) AF: 0.154 AC: 2356 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 63 AN: 3468

East Asian (EAS) AF: 0.192 AC: 992 AN: 5172

South Asian (SAS) AF: 0.0280 AC: 135 AN: 4822

European-Finnish (FIN) AF: 0.0103 AC: 109 AN: 10610

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0145 AC: 987 AN: 68002

Other (OTH) AF: 0.0336 AC: 71 AN: 2110

Alfa AF: 0.0307 Hom.: 69

Bravo AF: 0.0412

Asia WGS AF: 0.0960 AC: 334 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.0030
DANN	Benign	0.42
PhyloP100		-1.6
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: rs985421; hg19: chr11-121362316;