rs1247392012

Variant names:

• chr10-80170852-T-C
• rs1247392012
• NM_145868.2:c.119A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: ANXA11 NM_145868.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter 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 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 rank	MANE	Protein	UniProt
ANXA11	NM_145868.2	c.119A>G	p.Asp40Gly	missense_variant	Exon 4 of 16	ENST00000422982.8	NP_665875.1

Ensembl

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

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, single submitter

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	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
LIST_S2	Benign	0.74	.;.;T;T;T
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;.
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;