Variant rs949112777 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.137G>A(p.Arg46Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000369 in 1,353,758 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Consequence

SORL1
NM_003105.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.87

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=0.2855625).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6 link	c.137G>A	p.Arg46Gln	missense_variant	Exon 1 of 48	ENST00000260197.12	NP_003096.2	Q92673A0A024R3H2
SORL1-AS1	NR_183636.1 link	n.293+207C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SORL1	ENST00000260197.12 link	c.137G>A	p.Arg46Gln	missense_variant	Exon 1 of 48	1	NM_003105.6	ENSP00000260197.6	Q92673
SORL1	ENST00000532451.1 link	n.89G>A		non_coding_transcript_exon_variant	Exon 1 of 15	1
SORL1-AS1	ENST00000501964.1 link	n.339+207C>T		intron_variant	Intron 1 of 1	2
SORL1-AS1	ENST00000529160.1 link	n.245+207C>T		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000282

AC:

AN:

106352

Hom.:

AF XY:

0.0000502

AC XY:

AN XY:

59740

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000161

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000369

AC:

AN:

1353758

Hom.:

Cov.:

AF XY:

0.00000750

AC XY:

AN XY:

666282

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:

0.0000662

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.063

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.052

Eigen

Benign

-0.13

Eigen_PC

Benign

0.0052

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.29

MetaSVM

Uncertain

-0.021

MutationAssessor

Benign

1.8

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.19

REVEL

Uncertain

0.36

Sift

Uncertain

0.022

Sift4G

Uncertain

0.0080

Polyphen

0.11

Vest4

0.24

MutPred

0.58

Gain of catalytic residue at R46 (P = 0.1169);

MVP

0.75

MPC

0.29

ClinPred

0.27

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.53

gMVP

0.37

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over