11-121537246-T-C

Variant names:

• chr11-121537246-T-C
• rs11820794
• NM_003105.6:c.1685+4694T>C

Variant summary

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

The NM_003105.6(SORL1):​c.1685+4694T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0496 in 152,158 control chromosomes in the GnomAD database, including 274 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 0.050 (274 hom., cov: 31)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.168
• Publications: 3 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0957 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.1685+4694T>C		intron	N/A	NP_003096.2	Q92673

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	ENST00000260197.12	TSL:1 MANE Select	c.1685+4694T>C		intron	N/A	ENSP00000260197.6	Q92673
	SORL1	ENST00000532451.1	TSL:1	n.1637+4694T>C		intron	N/A
	SORL1	ENST00000905166.1		c.1685+4694T>C		intron	N/A	ENSP00000575225.1

Frequencies

GnomAD3 genomes AF: 0.0496 AC: 7537 AN: 152040 Hom.: 273 Cov.: 31

Gnomad AFR AF: 0.0982

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0352

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0321

Gnomad FIN AF: 0.0327

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0318

Gnomad OTH AF: 0.0541

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

GnomAD4 genome AF: 0.0496 AC: 7547 AN: 152158 Hom.: 274 Cov.: 31 AF XY: 0.0480 AC XY: 3571 AN XY: 74380

African (AFR) AF: 0.0982 AC: 4074 AN: 41490

American (AMR) AF: 0.0352 AC: 538 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 125 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0322 AC: 155 AN: 4820

European-Finnish (FIN) AF: 0.0327 AC: 347 AN: 10598

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0318 AC: 2159 AN: 67982

Other (OTH) AF: 0.0535 AC: 113 AN: 2112

Alfa AF: 0.0345 Hom.: 186

Bravo AF: 0.0517

Asia WGS AF: 0.0200 AC: 68 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.4
DANN	Benign	0.87
PhyloP100		0.17
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: rs11820794; hg19: chr11-121407955;