NM_145868.2:c.1457C>T

Variant names:

• chr10-80157642-G-A
• rs778082972
• NM_145868.2:c.1457C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_145868.2(ANXA11):​c.1457C>T​(p.Ser486Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000434 in 1,612,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: ANXA11 NM_145868.2 missense, splice_region
• Scores: Splicing: ADA: 0.9867
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.10
• Publications: 3 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: Genomics England PanelApp, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• inclusion body myopathy and brain white matter abnormalities

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS2: High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANXA11	NM_145868.2	c.1457C>T	p.Ser486Leu	missense_variant, splice_region_variant	Exon 15 of 16	ENST00000422982.8	NP_665875.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANXA11	ENST00000422982.8	c.1457C>T	p.Ser486Leu	missense_variant, splice_region_variant	Exon 15 of 16	1	NM_145868.2	ENSP00000404412.2

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.0000719 AC: 18 AN: 250462 AF XY: 0.0000517

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1460908 Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 726660

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.000627 AC: 28 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26054

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39670

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111382

Other (OTH) AF: 0.0000663 AC: 4 AN: 60352

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74254

African (AFR) AF: 0.0000242 AC: 1 AN: 41402

American (AMR) AF: 0.00164 AC: 25 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.000955 AC: 2 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000185

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Oct 24, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ANXA11 c.1457C>T (p.Ser486Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.2e-05 in 250462 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ANXA11 causing ANXA11-Related Disorders, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1457C>T in individuals affected with ANXA11-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1366578). Based on the evidence outlined above, the variant was classified as uncertain significance. -

ANXA11-related disorder Uncertain:1

Aug 15, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ANXA11 c.1457C>T variant is predicted to result in the amino acid substitution p.Ser486Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.045% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-81917398-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases Uncertain:1

Dec 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1457C>T (p.S486L) alteration is located in exon 14 (coding exon 13) of the ANXA11 gene. This alteration results from a C to T substitution at nucleotide position 1457, causing the serine (S) at amino acid position 486 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 486 of the ANXA11 protein (p.Ser486Leu). This variant is present in population databases (rs778082972, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ANXA11-related conditions. ClinVar contains an entry for this variant (Variation ID: 1366578). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.51
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.059	T;T;.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	.;.;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L;.;L
PhyloP100		4.1
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.2	D;D;.;D
REVEL	Benign	0.10
Sift	Uncertain	0.0080	D;D;.;D
Sift4G	Uncertain	0.049	D;D;T;D
Polyphen		0.98	D;D;.;D
Vest4		0.21
MutPred		0.31		Loss of disorder (P = 0.0138);Loss of disorder (P = 0.0138);.;Loss of disorder (P = 0.0138);
MVP		0.35
MPC		0.19
ClinPred		0.40	T
GERP RS		4.9
Varity_R		0.22
gMVP		0.31
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.060		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: rs778082972; hg19: chr10-81917398; COSMIC: COSV55417162;