rs1247392012

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PS3 PM2 PM5 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 (★). ClinVar reports functional evidence for this variant: "SCV002119960: Experimental studies have shown that this missense change affects ANXA11 function (PMID:28469040, 33087501)." and additional evidence is available in ClinVar. 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, single submitter P:3
• Conservation: PhyloP100: 4.81
• Publications: 32 publications found

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: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
• inclusion body myopathy and brain white matter abnormalities

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002119960: Experimental studies have shown that this missense change affects ANXA11 function (PMID: 28469040, 33087501).; SCV004103073: 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).
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145868.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANXA11	NM_145868.2	MANE Select	c.119A>G	p.Asp40Gly	missense	Exon 4 of 16	NP_665875.1	P50995-1
	ANXA11	NM_001157.3		c.119A>G	p.Asp40Gly	missense	Exon 3 of 15	NP_001148.1	P50995-1
	ANXA11	NM_001278407.2		c.119A>G	p.Asp40Gly	missense	Exon 5 of 17	NP_001265336.1	Q5T0G8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANXA11	ENST00000422982.8	TSL:1 MANE Select	c.119A>G	p.Asp40Gly	missense	Exon 4 of 16	ENSP00000404412.2	P50995-1
	ANXA11	ENST00000372231.7	TSL:1	c.119A>G	p.Asp40Gly	missense	Exon 3 of 15	ENSP00000361305.3	P50995-1
	ANXA11	ENST00000438331.5	TSL:1	c.119A>G	p.Asp40Gly	missense	Exon 5 of 17	ENSP00000398610.1	P50995-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000114 AC: 2 AN: 174858 AF XY: 0.00

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

African (AFR) AF: 0.00 AC: 0 AN: 29908

American (AMR) AF: 0.00 AC: 0 AN: 29362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20828

East Asian (EAS) AF: 0.00 AC: 0 AN: 36876

South Asian (SAS) AF: 0.00 AC: 0 AN: 71010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5390

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1075040

Other (OTH) AF: 0.00 AC: 0 AN: 56768

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Amyotrophic lateral sclerosis type 23 (1)
1	-	-	ANXA11-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.13
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.18
Sift	Benign	0.55	T
Sift4G	Benign	0.51	T
Polyphen		0.97	D
Vest4		0.64
MutPred		0.30		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
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1247392012; hg19: chr10-81930608;