rs142083484

Positions:

chr10-80170859-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PP5_Very_StrongBP4BS2_Supporting

The NM_145868.2(ANXA11):c.112G>A(p.Gly38Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000748 in 1,537,436 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 pathogenic (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

ANXA11
NM_145868.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.75

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 Likely_pathogenic. Variant got 6 ACMG points.

PP5

Variant 10-80170859-C-T is Pathogenic according to our data. Variant chr10-80170859-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.28837082). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANXA11	NM_145868.2 linkuse as main transcript	c.112G>A	p.Gly38Arg	missense_variant	4/16	ENST00000422982.8	NP_665875.1	P50995-1Q5T0G8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANXA11	ENST00000422982.8 linkuse as main transcript	c.112G>A	p.Gly38Arg	missense_variant	4/16	1	NM_145868.2	ENSP00000404412.2		P50995-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000882

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000381

AC:

AN:

183494

Hom.:

AF XY:

0.0000509

AC XY:

AN XY:

98276

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:

0.0000563

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000679

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000780

AC:

108

AN:

1385254

Hom.:

Cov.:

AF XY:

0.0000803

AC XY:

AN XY:

685132

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:

0.0000548

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000918

Gnomad4 OTH exome

AF:

0.0000874

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000453

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ANXA11: PM1, PS3:Moderate, PS4:Moderate, PM2:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 38 of the ANXA11 protein (p.Gly38Arg). This variant is present in population databases (rs142083484, gnomAD 0.008%). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 28469040, 29650794, 33087501, 33218681; Invitae). ClinVar contains an entry for this variant (Variation ID: 488354). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects ANXA11 function (PMID: 28469040, 30109997, 33087501). For these reasons, this variant has been classified as Pathogenic. -

ANXA11-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2024

The ANXA11 c.112G>A variant is predicted to result in the amino acid substitution p.Gly38Arg. This variant has been reported to be causative for amyotrophic lateral sclerosis (ALS, Smith et al. 2017. PubMed ID: 28469040; Müller et al. 2018. PubMed ID: 29650794; Teyssou et al. 2020. PubMed ID: 33218681). In vitro functional studies have shown the p.Gly38Arg variant leads to stress granule formation, and this supports its pathogenicity in ALS (Nahm et al. 2020. PubMed ID: 33087501). This variant is reported in 0.0077% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Amyotrophic lateral sclerosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Neurogenomics Lab, Neuroscience Institute, University Of Cape Town

May 22, 2024

PM2_supporting: the highest population allele frequency in gnomAD v4.0 is 0.00007705 (0.008%; 8/103830 alleles in European non-Finnish population) and in gnomAD v3.1.2 is 0.0004798 (0.048%; 1/2084 alleles in Other population) and the variant is absent from an internal database of 1412 alleles. PP3 met- multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM1 met- variant is located in the N-terminal low complexity domain of ANXA11 near the calcyclin binding region and clusters with other pathogenic variants (p.P35A, p.P36R, p.D40G/p.D40Y). PS3_supporting- various functional studies provide evidence that this variant affects protein function (PMID 33087501, 30109997, 28469040). PS4_moderate- variant identified in 7 unrelated probands with consistent phenotype for disorder (PMID 35047667, 33218681, 33087501, 29650794, 28469040, clinical testing). -

Amyotrophic lateral sclerosis type 23

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.084

T;T;.;T;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.89

.;.;D;D;D

M_CAP

Benign

0.024

MetaRNN

Benign

0.29

T;T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.7

M;M;.;M;.

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.6

N;N;D;N;D

REVEL

Benign

0.26

Sift

Uncertain

0.0060

D;D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D;D

Polyphen

1.0

D;D;.;D;.

Vest4

0.80

MutPred

0.41

Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);.;Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);

MVP

0.28

MPC

0.068

ClinPred

0.28

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.51

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