11-121555498-T-G

Variant names:

• chr11-121555498-T-G
• rs556349
• NM_003105.6:c.2571+180T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003105.6(SORL1):​c.2571+180T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 151,982 control chromosomes in the GnomAD database, including 23,373 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 0.52 (23373 hom., cov: 32)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.23
• Publications: 10 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 (NFE) allele frequency at 95% confidence interval = 0.674 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	NM_003105.6	MANE Select	c.2571+180T>G		intron	N/A	NP_003096.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	ENST00000260197.12	TSL:1 MANE Select	c.2571+180T>G		intron	N/A	ENSP00000260197.6
	SORL1	ENST00000905166.1		c.2571+180T>G		intron	N/A	ENSP00000575225.1
	SORL1	ENST00000905167.1		c.2454+180T>G		intron	N/A	ENSP00000575226.1

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79654 AN: 151864 Hom.: 23377 Cov.: 32

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.717

Gnomad AMR AF: 0.437

Gnomad ASJ AF: 0.674

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.679

Gnomad OTH AF: 0.558

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

GnomAD4 genome AF: 0.524 AC: 79662 AN: 151982 Hom.: 23373 Cov.: 32 AF XY: 0.519 AC XY: 38556 AN XY: 74266

African (AFR) AF: 0.298 AC: 12361 AN: 41454

American (AMR) AF: 0.437 AC: 6670 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.674 AC: 2338 AN: 3468

East Asian (EAS) AF: 0.233 AC: 1206 AN: 5178

South Asian (SAS) AF: 0.396 AC: 1908 AN: 4820

European-Finnish (FIN) AF: 0.672 AC: 7059 AN: 10508

Middle Eastern (MID) AF: 0.579 AC: 169 AN: 292

European-Non Finnish (NFE) AF: 0.679 AC: 46135 AN: 67964

Other (OTH) AF: 0.552 AC: 1165 AN: 2112

Alfa AF: 0.606 Hom.: 24614

Bravo AF: 0.497

Asia WGS AF: 0.324 AC: 1127 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.16
DANN	Benign	0.41
PhyloP100		-2.2
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: rs556349; hg19: chr11-121426207;