11-121581231-C-T

Variant names:

• chr11-121581231-C-T
• rs7116734
• NM_003105.6:c.3581-2227C>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.3581-2227C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 152,098 control chromosomes in the GnomAD database, including 23,747 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 0.54 (23747 hom., cov: 33)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.514
• Publications: 4 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.751 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.3581-2227C>T		intron_variant	Intron 25 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.3581-2227C>T		intron_variant	Intron 25 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000525532.5	c.413-2227C>T		intron_variant	Intron 5 of 27	2		ENSP00000434634.1
SORL1	ENST00000534286.5	c.311-2227C>T		intron_variant	Intron 2 of 24	2		ENSP00000436447.1
SORL1	ENST00000532694.5	c.119-2227C>T		intron_variant	Intron 2 of 24	2		ENSP00000432131.1

Frequencies

GnomAD3 genomes AF: 0.538 AC: 81710 AN: 151980 Hom.: 23701 Cov.: 33

Gnomad AFR AF: 0.720

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.354

Gnomad EAS AF: 0.771

Gnomad SAS AF: 0.666

Gnomad FIN AF: 0.484

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.516

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

GnomAD4 genome AF: 0.538 AC: 81815 AN: 152098 Hom.: 23747 Cov.: 33 AF XY: 0.547 AC XY: 40672 AN XY: 74338

African (AFR) AF: 0.720 AC: 29871 AN: 41492

American (AMR) AF: 0.611 AC: 9346 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 1226 AN: 3464

East Asian (EAS) AF: 0.771 AC: 3987 AN: 5174

South Asian (SAS) AF: 0.664 AC: 3201 AN: 4822

European-Finnish (FIN) AF: 0.484 AC: 5104 AN: 10544

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.404 AC: 27473 AN: 67988

Other (OTH) AF: 0.522 AC: 1104 AN: 2116

Alfa AF: 0.491 Hom.: 7463

Bravo AF: 0.555

Asia WGS AF: 0.714 AC: 2484 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.0
DANN	Benign	0.75
PhyloP100		-0.51
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: rs7116734; hg19: chr11-121451940;