rs1049550

Positions:

• chr10-80166946-G-A
• chr10-80166946-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BA1

The NM_145868.2(ANXA11):​c.688C>T​(p.Arg230Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.415 in 1,605,962 control chromosomes in the GnomAD database, including 142,304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.37 (11314 hom., cov: 32)
  • Exomes 𝑓: 0.42 (130990 hom.)
• Consequence: ANXA11 NM_145868.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.63

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, BayesDel_noAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=1.5074015E-4).
• BP6: Variant 10-80166946-G-A is Benign according to our data. Variant chr10-80166946-G-A is described in ClinVar as [Benign]. Clinvar id is 1297185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANXA11	NM_145868.2	c.688C>T	p.Arg230Cys	missense_variant	7/16	ENST00000422982.8	NP_665875.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANXA11	ENST00000422982.8	c.688C>T	p.Arg230Cys	missense_variant	7/16	1	NM_145868.2	ENSP00000404412.2

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55862 AN: 151812 Hom.: 11312 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.387

GnomAD3 exomes AF: 0.420 AC: 100378 AN: 239214 Hom.: 21983 AF XY: 0.418 AC XY: 54124 AN XY: 129332

Gnomad AFR exome AF: 0.199

Gnomad AMR exome AF: 0.449

Gnomad ASJ exome AF: 0.376

Gnomad EAS exome AF: 0.668

Gnomad SAS exome AF: 0.359

Gnomad FIN exome AF: 0.447

Gnomad NFE exome AF: 0.416

Gnomad OTH exome AF: 0.427

GnomAD4 exome AF: 0.420 AC: 610391 AN: 1454032 Hom.: 130990 Cov.: 42 AF XY: 0.418 AC XY: 302214 AN XY: 722822

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.446

Gnomad4 ASJ exome AF: 0.379

Gnomad4 EAS exome AF: 0.651

Gnomad4 SAS exome AF: 0.359

Gnomad4 FIN exome AF: 0.450

Gnomad4 NFE exome AF: 0.422

Gnomad4 OTH exome AF: 0.411

GnomAD4 genome AF: 0.368 AC: 55855 AN: 151930 Hom.: 11314 Cov.: 32 AF XY: 0.371 AC XY: 27546 AN XY: 74208

Gnomad4 AFR AF: 0.199

Gnomad4 AMR AF: 0.423

Gnomad4 ASJ AF: 0.378

Gnomad4 EAS AF: 0.663

Gnomad4 SAS AF: 0.358

Gnomad4 FIN AF: 0.454

Gnomad4 NFE AF: 0.421

Gnomad4 OTH AF: 0.385

Alfa AF: 0.410 Hom.: 23699

Bravo AF: 0.360

TwinsUK AF: 0.427 AC: 1585

ALSPAC AF: 0.408 AC: 1572

ESP6500AA AF: 0.202 AC: 891

ESP6500EA AF: 0.409 AC: 3521

ExAC AF: 0.404 AC: 48980

Asia WGS AF: 0.443 AC: 1538 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 21562576, 20093723, 19165924, 17000706, 24032725) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inclusion body myopathy and brain white matter abnormalities Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T;T;.;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;.;D;D
MetaRNN	Benign	0.00015	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Pathogenic	3.7	H;H;.;H
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.5	D;D;.;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.017	D;D;.;D
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.33
MPC		0.43
ClinPred		0.093	T
GERP RS		4.3
Varity_R		0.51
gMVP		0.88

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: rs1049550; hg19: chr10-81926702; COSMIC: COSV55416425; COSMIC: COSV55416425;