dbSNP rs1049550: ANXA11:p.Arg230Cys (chr10-80166946-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBA1

The NM_145868.2(ANXA11):c.688C>T(p.Arg230Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.415 in 1,605,962 control chromosomes in the GnomAD database, including 142,304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R230S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.37 ( 11314 hom., cov: 32)

Exomes 𝑓: 0.42 ( 130990 hom. )

Consequence

ANXA11
NM_145868.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 7.63

Publications

88 publications found

Variant links:

Genes affected

ANXA11 (HGNC:535): (annexin A11) This gene encodes a member of the annexin family, a group of calcium-dependent phospholipid-binding proteins. Annexins have unique N-terminal domains and conserved C-terminal domains, which contain calcium-dependent phospholipid-binding sites. The encoded protein is a 56-kD antigen recognized by sera from patients with various autoimmune diseases. Several transcript variants encoding two different isoforms have been identified. [provided by RefSeq, Dec 2015]

ANXA11 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis type 23
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
inclusion body myopathy and brain white matter abnormalities
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ANXA11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, BayesDel_noAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=1.5074015E-4).

BP6

Variant 10-80166946-G-A is Benign according to our data. Variant chr10-80166946-G-A is described in ClinVar as Benign. ClinVar VariationId is 1297185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145868.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANXA11	NM_145868.2	MANE Select	c.688C>T	p.Arg230Cys	missense	Exon 7 of 16	NP_665875.1	P50995-1
ANXA11	NM_001157.3		c.688C>T	p.Arg230Cys	missense	Exon 6 of 15	NP_001148.1	P50995-1
ANXA11	NM_001278407.2		c.688C>T	p.Arg230Cys	missense	Exon 8 of 17	NP_001265336.1	Q5T0G8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANXA11	ENST00000422982.8	TSL:1 MANE Select	c.688C>T	p.Arg230Cys	missense	Exon 7 of 16	ENSP00000404412.2	P50995-1
ANXA11	ENST00000372231.7	TSL:1	c.688C>T	p.Arg230Cys	missense	Exon 6 of 15	ENSP00000361305.3	P50995-1
ANXA11	ENST00000438331.5	TSL:1	c.688C>T	p.Arg230Cys	missense	Exon 8 of 17	ENSP00000398610.1	P50995-1

Frequencies

GnomAD3 genomes

AF:

0.368

AC:

55862

AN:

151812

Hom.:

11312

Cov.:

show subpopulations

Gnomad AFR

AF:

0.199

Gnomad AMI

AF:

0.470

Gnomad AMR

AF:

0.423

Gnomad ASJ

AF:

0.378

Gnomad EAS

AF:

0.663

Gnomad SAS

AF:

0.359

Gnomad FIN

AF:

0.454

Gnomad MID

AF:

0.361

Gnomad NFE

AF:

0.421

Gnomad OTH

AF:

0.387

GnomAD2 exomes

AF:

0.420

AC:

100378

AN:

239214

AF XY:

0.418

show subpopulations

Gnomad AFR exome

AF:

0.199

Gnomad AMR exome

AF:

0.449

Gnomad ASJ exome

AF:

0.376

Gnomad EAS exome

AF:

0.668

Gnomad FIN exome

AF:

0.447

Gnomad NFE exome

AF:

0.416

Gnomad OTH exome

AF:

0.427

GnomAD4 exome

AF:

0.420

AC:

610391

AN:

1454032

Hom.:

130990

Cov.:

AF XY:

0.418

AC XY:

302214

AN XY:

722822

show subpopulations

African (AFR)

AF:

0.192

AC:

6407

AN:

33338

American (AMR)

AF:

0.446

AC:

19584

AN:

43942

Ashkenazi Jewish (ASJ)

AF:

0.379

AC:

9882

AN:

26060

East Asian (EAS)

AF:

0.651

AC:

25635

AN:

39364

South Asian (SAS)

AF:

0.359

AC:

30561

AN:

85134

European-Finnish (FIN)

AF:

0.450

AC:

23267

AN:

51674

Middle Eastern (MID)

AF:

0.404

AC:

2315

AN:

5726

European-Non Finnish (NFE)

AF:

0.422

AC:

468018

AN:

1108676

Other (OTH)

AF:

0.411

AC:

24722

AN:

60118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

17169

34337

51506

68674

85843

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14310

28620

42930

57240

71550

<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:

0.368

AC:

55855

AN:

151930

Hom.:

11314

Cov.:

AF XY:

0.371

AC XY:

27546

AN XY:

74208

show subpopulations

African (AFR)

AF:

0.199

AC:

8247

AN:

41436

American (AMR)

AF:

0.423

AC:

6460

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.378

AC:

1311

AN:

3468

East Asian (EAS)

AF:

0.663

AC:

3405

AN:

5138

South Asian (SAS)

AF:

0.358

AC:

1722

AN:

4812

European-Finnish (FIN)

AF:

0.454

AC:

4774

AN:

10522

Middle Eastern (MID)

AF:

0.371

AC:

109

AN:

294

European-Non Finnish (NFE)

AF:

0.421

AC:

28587

AN:

67958

Other (OTH)

AF:

0.385

AC:

811

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1740

3479

5219

6958

8698

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

538

1076

1614

2152

2690

<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:

0.403

Hom.:

52435

Bravo

AF:

0.360

TwinsUK

AF:

0.427

AC:

1585

ALSPAC

AF:

0.408

AC:

1572

ESP6500AA

AF:

0.202

AC:

891

ESP6500EA

AF:

0.409

AC:

3521

ExAC

AF:

0.404

AC:

48980

Asia WGS

AF:

0.443

AC:

1538

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Inclusion body myopathy and brain white matter abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.13

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.00015

MetaSVM

Benign

-0.93

MutationAssessor

Pathogenic

3.7

PhyloP100

7.6

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.5

REVEL

Uncertain

0.36

Sift

Uncertain

0.017

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.33

MPC

0.43

ClinPred

0.093

GERP RS

4.3

Varity_R

0.51

gMVP

0.88

Mutation Taster

=84/16

polymorphism (auto)

(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

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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