NM_003105.6:c.*2473C>G

Variant names:

• chr11-121632036-C-G
• rs1131497
• NM_003105.6:c.*2473C>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.*2473C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 152,050 control chromosomes in the GnomAD database, including 10,967 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 0.35 (10967 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SORL1 NM_003105.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0970
• Publications: 25 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=-0.72).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.*2473C>G		3_prime_UTR_variant	Exon 48 of 48	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.*2473C>G		3_prime_UTR_variant	Exon 48 of 48	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000530365.1	n.779C>G		non_coding_transcript_exon_variant	Exon 2 of 2	5

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53266 AN: 151932 Hom.: 10956 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.579

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.425

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.351

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.351 AC: 53294 AN: 152050 Hom.: 10967 Cov.: 32 AF XY: 0.355 AC XY: 26382 AN XY: 74316

African (AFR) AF: 0.126 AC: 5234 AN: 41492

American (AMR) AF: 0.393 AC: 6010 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1330 AN: 3468

East Asian (EAS) AF: 0.578 AC: 2990 AN: 5172

South Asian (SAS) AF: 0.515 AC: 2485 AN: 4822

European-Finnish (FIN) AF: 0.425 AC: 4485 AN: 10562

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.435 AC: 29522 AN: 67940

Other (OTH) AF: 0.359 AC: 758 AN: 2112

Alfa AF: 0.395 Hom.: 1670

Bravo AF: 0.336

Asia WGS AF: 0.505 AC: 1756 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.6
DANN	Benign	0.77
PhyloP100		0.097
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1131497; hg19: chr11-121502745;