Variant rs1247392012 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_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 (★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-80170852-T-C is Pathogenic according to our data. Variant chr10-80170852-T-C is described in ClinVar as [Pathogenic]. Clinvar id 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/exons	MANE	Protein	UniProt
ANXA11	NM_145868.2 linkuse as main transcript	c.119A>G	p.Asp40Gly	missense_variant	4/16	ENST00000422982.8	NP_665875.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANXA11	ENST00000422982.8 linkuse as main transcript	c.119A>G	p.Asp40Gly	missense_variant	4/16	1	NM_145868.2	ENSP00000404412	P2	P50995-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000114

AC:

AN:

174858

Hom.:

AF XY:

0.00

AC XY:

AN XY:

93260

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:

0.00

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

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:

0.00000186

Gnomad4 OTH exome

AF:

0.00

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

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2023

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 29, 2018

- -

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

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;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

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

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