rs1247392012

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM2PM5PP5_ModerateBP4

The NM_145868.2(ANXA11):c.119A>G(p.Asp40Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000145 in 1,376,080 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D40Y) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

ANXA11
NM_145868.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 4.81

Publications

30 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: Genomics England PanelApp, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
inclusion body myopathy and brain white matter abnormalities
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
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: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-80170853-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 802593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 10-80170852-T-C is Pathogenic according to our data. Variant chr10-80170852-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 488353.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.21516684). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANXA11	NM_145868.2 link	c.119A>G	p.Asp40Gly	missense_variant	Exon 4 of 16	ENST00000422982.8	NP_665875.1	P50995-1Q5T0G8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANXA11	ENST00000422982.8 link	c.119A>G	p.Asp40Gly	missense_variant	Exon 4 of 16	1	NM_145868.2	ENSP00000404412.2		P50995-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000114

AC:

AN:

174858

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000234

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1376080

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

679800

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29908

American (AMR)

AF:

0.00

AC:

AN:

29362

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20828

East Asian (EAS)

AF:

0.00

AC:

AN:

36876

South Asian (SAS)

AF:

0.00

AC:

AN:

71010

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50898

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5390

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1075040

Other (OTH)

AF:

0.00

AC:

AN:

56768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ANXA11-related disorder

Pathogenic:1

Jan 16, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ANXA11 c.119A>G variant is predicted to result in the amino acid substitution p.Asp40Gly. This variant has been reported in individuals with amyotrophic lateral sclerosis (ALS) or ALS-frontotemporal dementia (ALS-FTD) (Smith et al. 2017. PubMed ID: 28469040; Zhang et al. 2018. PubMed ID: 29845112; Nahm et al. 2020. PubMed ID: 33087501; Wang et al. 2022. PubMed ID: 36226077). It was reported to segregate with disease in at least two families (Smith et al. 2017. PubMed ID: 28469040). Experimental studies are consistent with the p.Asp40Gly substitution impacting protein function (Smith et al. 2017. PubMed ID: 28469040; Nahm et al. 2020. PubMed ID: 33087501). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Jan 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ANXA11 function (PMID: 28469040, 33087501). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 488353). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 28469040, 29845112, 33087501). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 40 of the ANXA11 protein (p.Asp40Gly). -

Amyotrophic lateral sclerosis type 23

Pathogenic:1

Jan 29, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0088

T;T;.;T;.

Eigen

Benign

0.13

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.74

.;.;T;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.22

T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.2

L;L;.;L;.

PhyloP100

4.8

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.24

N;N;.;N;D

REVEL

Benign

0.18

Sift

Benign

0.55

T;T;.;T;D

Sift4G

Benign

0.51

T;T;T;T;T

Polyphen

0.97

D;D;.;D;.

Vest4

0.64

MutPred

0.30

Loss of stability (P = 0.0533);Loss of stability (P = 0.0533);.;Loss of stability (P = 0.0533);Loss of stability (P = 0.0533);

MVP

0.21

MPC

0.074

ClinPred

0.31

GERP RS

4.7

Varity_R

0.19

gMVP

0.35

Mutation Taster

=7/93

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over