NM_003105.6:c.940-6917C>T

Variant names:

• chr11-121506086-C-T
• rs7105365
• NM_003105.6:c.940-6917C>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.940-6917C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 151,880 control chromosomes in the GnomAD database, including 7,604 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 0.30 (7604 hom., cov: 32)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.490
• 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=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.940-6917C>T		intron_variant	Intron 6 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.940-6917C>T		intron_variant	Intron 6 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000532451.1	n.892-6917C>T		intron_variant	Intron 6 of 14	1

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45097 AN: 151760 Hom.: 7604 Cov.: 32

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.486

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.299

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

GnomAD4 genome AF: 0.297 AC: 45088 AN: 151880 Hom.: 7604 Cov.: 32 AF XY: 0.296 AC XY: 21968 AN XY: 74218

African (AFR) AF: 0.150 AC: 6227 AN: 41402

American (AMR) AF: 0.269 AC: 4101 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1548 AN: 3468

East Asian (EAS) AF: 0.118 AC: 612 AN: 5188

South Asian (SAS) AF: 0.298 AC: 1436 AN: 4816

European-Finnish (FIN) AF: 0.386 AC: 4068 AN: 10530

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.381 AC: 25908 AN: 67920

Other (OTH) AF: 0.296 AC: 621 AN: 2100

Alfa AF: 0.285 Hom.: 1615

Bravo AF: 0.279

Asia WGS AF: 0.192 AC: 667 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.74
DANN	Benign	0.29
PhyloP100		-0.49
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: rs7105365; hg19: chr11-121376795;