NM_003105.6:c.402+1255G>A

Variant names:

• chr11-121471378-G-A
• rs11218301
• NM_003105.6:c.402+1255G>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+1255G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 152,040 control chromosomes in the GnomAD database, including 8,809 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 0.32 (8809 hom., cov: 32)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10
• Publications: 9 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 (NFE) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003105.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	NM_003105.6	MANE Select	c.402+1255G>A		intron	N/A	NP_003096.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	ENST00000260197.12	TSL:1 MANE Select	c.402+1255G>A		intron	N/A	ENSP00000260197.6
	SORL1	ENST00000532451.1	TSL:1	n.354+1255G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48292 AN: 151922 Hom.: 8812 Cov.: 32

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.426

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.410

Gnomad OTH AF: 0.325

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

GnomAD4 genome AF: 0.317 AC: 48271 AN: 152040 Hom.: 8809 Cov.: 32 AF XY: 0.317 AC XY: 23540 AN XY: 74290

African (AFR) AF: 0.154 AC: 6406 AN: 41478

American (AMR) AF: 0.286 AC: 4378 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1698 AN: 3466

East Asian (EAS) AF: 0.125 AC: 649 AN: 5176

South Asian (SAS) AF: 0.313 AC: 1509 AN: 4824

European-Finnish (FIN) AF: 0.426 AC: 4483 AN: 10534

Middle Eastern (MID) AF: 0.462 AC: 135 AN: 292

European-Non Finnish (NFE) AF: 0.410 AC: 27851 AN: 67962

Other (OTH) AF: 0.321 AC: 678 AN: 2110

Alfa AF: 0.378 Hom.: 19150

Bravo AF: 0.298

Asia WGS AF: 0.205 AC: 713 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.057
DANN	Benign	0.73
PhyloP100		-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: rs11218301; hg19: chr11-121342087;