Variant 11-121452346-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003105.6(SORL1):c.15C>A(p.Ser5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,400,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

SORL1
NM_003105.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.999

Variant links:

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 links:

SORL1-AS1 (HGNC:55594): (SORL1 antisense RNA 1)

SORL1-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3047356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORL1	NM_003105.6 linkuse as main transcript	c.15C>A	p.Ser5Arg	missense_variant	1/48	ENST00000260197.12
SORL1-AS1	NR_183636.1 linkuse as main transcript	n.293+329G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SORL1	ENST00000260197.12 linkuse as main transcript	c.15C>A	p.Ser5Arg	missense_variant	1/48	1	NM_003105.6	P1
SORL1-AS1	ENST00000501964.1 linkuse as main transcript	n.339+329G>T		intron_variant, non_coding_transcript_variant		2
SORL1-AS1	ENST00000529160.1 linkuse as main transcript	n.245+329G>T		intron_variant, non_coding_transcript_variant		2
SORL1	ENST00000532451.1 linkuse as main transcript			upstream_gene_variant		1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000286

AC:

AN:

1400534

Hom.:

Cov.:

AF XY:

0.00000432

AC XY:

AN XY:

694068

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000368

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2023

The c.15C>A (p.S5R) alteration is located in exon 1 (coding exon 1) of the SORL1 gene. This alteration results from a C to A substitution at nucleotide position 15, causing the serine (S) at amino acid position 5 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.073

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.053

Eigen

Benign

-0.042

Eigen_PC

Benign

0.050

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.69

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.30

MetaSVM

Uncertain

0.061

MutationAssessor

Benign

1.4

MutationTaster

Benign

0.99

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.26

REVEL

Uncertain

0.33

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0090

Polyphen

0.74

Vest4

0.19

MutPred

0.17

Loss of phosphorylation at S5 (P = 0.0031);

MVP

0.84

MPC

0.91

ClinPred

0.75

GERP RS

3.8

Varity_R

0.30

gMVP

0.54

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over