rs1247392012

chr10-80170852-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM2 PM5 PP5_Very_Strong BP4

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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.81

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 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 [Likely_pathogenic]. Clinvar id 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 id is 488353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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	UniProt
ANXA11	NM_145868.2	c.119A>G	p.Asp40Gly	missense_variant	4/16	ENST00000422982.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANXA11	ENST00000422982.8	c.119A>G	p.Asp40Gly	missense_variant	4/16	1	NM_145868.2	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000114 AC: 2 AN: 174858 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 93260

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: 2 AN: 1376080 Hom.: 0 Cov.: 30 AF XY: 0.00000147 AC XY: 1 AN XY: 679800

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.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ANXA11-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

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

Invitae

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	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	22
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	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.2	L;L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.70	T
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	T
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

Other links and lift over

dbSNP: rs1247392012; hg19: chr10-81930608;