chr11-121452467-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_003105.6(SORL1):c.136C>G(p.Arg46Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,507,152 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R46P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

SORL1
NM_003105.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.31

Publications

1 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014997691).

BP6

Variant 11-121452467-C-G is Benign according to our data. Variant chr11-121452467-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1532873.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000755 (115/152232) while in subpopulation AFR AF = 0.00274 (114/41582). AF 95% confidence interval is 0.00233. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 115 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003105.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	NM_003105.6	MANE Select	c.136C>G	p.Arg46Gly	missense	Exon 1 of 48	NP_003096.2	Q92673
	SORL1-AS1	NR_183636.1	MANE Select	n.293+208G>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SORL1	ENST00000260197.12	TSL:1 MANE Select	c.136C>G	p.Arg46Gly	missense	Exon 1 of 48	ENSP00000260197.6	Q92673
SORL1	ENST00000532451.1	TSL:1	n.88C>G		non_coding_transcript_exon	Exon 1 of 15
SORL1-AS1	ENST00000529160.2	TSL:2 MANE Select	n.293+208G>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000756

AC:

115

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00275

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000131

AC:

AN:

107116

AF XY:

0.000150

show subpopulations

Gnomad AFR exome

AF:

0.00277

Gnomad AMR exome

AF:

0.000371

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000341

GnomAD4 exome

AF:

0.0000768

AC:

104

AN:

1354920

Hom.:

Cov.:

AF XY:

0.0000600

AC XY:

AN XY:

666908

show subpopulations

African (AFR)

AF:

0.00327

AC:

AN:

27560

American (AMR)

AF:

0.000258

AC:

AN:

31012

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23794

East Asian (EAS)

AF:

0.00

AC:

AN:

30784

South Asian (SAS)

AF:

0.0000132

AC:

AN:

75586

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44940

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4366

European-Non Finnish (NFE)

AF:

9.43e-7

AC:

AN:

1060934

Other (OTH)

AF:

0.0000715

AC:

AN:

55944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000755

AC:

115

AN:

152232

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00274

AC:

114

AN:

41582

American (AMR)

AF:

0.0000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67980

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000352

Hom.:

Bravo

AF:

0.000873

ExAC

AF:

0.000171

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

SORL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.074

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.063

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.77

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.064

MutationAssessor

Benign

1.8

PhyloP100

1.3

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.39

REVEL

Uncertain

0.41

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0030

Polyphen

0.0

Vest4

0.38

MutPred

0.59

Loss of disorder (P = 0.1728)

MVP

0.83

MPC

0.33

ClinPred

0.067

GERP RS

3.9

PromoterAI

-0.035

Neutral

(source)

Varity_R

0.54

gMVP

0.55

Mutation Taster

=78/22

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over