11-121616663-C-T

Variant names:

• chr11-121616663-C-T
• rs10790447
• NM_003105.6:c.5604+1608C>T

Variant summary

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

The NM_003105.6(SORL1):​c.5604+1608C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 152,194 control chromosomes in the GnomAD database, including 12,135 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 0.37 (12135 hom., cov: 33)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.447
• Publications: 2 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=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.5604+1608C>T		intron_variant	Intron 41 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.5604+1608C>T		intron_variant	Intron 41 of 47	1	NM_003105.6	ENSP00000260197.6

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56553 AN: 152076 Hom.: 12124 Cov.: 33

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.339

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.561

Gnomad SAS AF: 0.567

Gnomad FIN AF: 0.544

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.385

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

GnomAD4 genome AF: 0.372 AC: 56585 AN: 152194 Hom.: 12135 Cov.: 33 AF XY: 0.382 AC XY: 28433 AN XY: 74414

African (AFR) AF: 0.155 AC: 6430 AN: 41540

American (AMR) AF: 0.456 AC: 6975 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1044 AN: 3472

East Asian (EAS) AF: 0.560 AC: 2891 AN: 5164

South Asian (SAS) AF: 0.566 AC: 2733 AN: 4828

European-Finnish (FIN) AF: 0.544 AC: 5762 AN: 10596

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.434 AC: 29522 AN: 67988

Other (OTH) AF: 0.391 AC: 824 AN: 2106

Alfa AF: 0.407 Hom.: 2720

Bravo AF: 0.348

Asia WGS AF: 0.531 AC: 1850 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.22
DANN	Benign	0.65
PhyloP100		-0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10790447; hg19: chr11-121487372; COSMIC: COSV52763147;