4-78597321-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005139.3(ANXA3):c.637T>A(p.Phe213Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000875 in 1,599,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

ANXA3
NM_005139.3 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.27

Variant links:

Genes affected

ANXA3 (HGNC:541): (annexin A3) This gene encodes a member of the annexin family. Members of this calcium-dependent phospholipid-binding protein family play a role in the regulation of cellular growth and in signal transduction pathways. This protein functions in the inhibition of phopholipase A2 and cleavage of inositol 1,2-cyclic phosphate to form inositol 1-phosphate. This protein may also play a role in anti-coagulation. [provided by RefSeq, Jul 2008]

ANXA3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.42078578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANXA3	NM_005139.3 linkuse as main transcript	c.637T>A	p.Phe213Ile	missense_variant, splice_region_variant	10/13	ENST00000264908.11
ANXA3	XM_047450154.1 linkuse as main transcript	c.637T>A	p.Phe213Ile	missense_variant, splice_region_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ANXA3	ENST00000264908.11 linkuse as main transcript	c.637T>A	p.Phe213Ile	missense_variant, splice_region_variant	10/13	1	NM_005139.3	P1
ANXA3	ENST00000503570.6 linkuse as main transcript	c.520T>A	p.Phe174Ile	missense_variant, splice_region_variant	11/14	5
ANXA3	ENST00000512884.5 linkuse as main transcript	c.520T>A	p.Phe174Ile	missense_variant, splice_region_variant	9/12	5
ANXA3	ENST00000505805.1 linkuse as main transcript	n.249T>A		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000203

AC:

AN:

246564

Hom.:

AF XY:

0.0000300

AC XY:

AN XY:

133214

show subpopulations

Gnomad AFR exome

AF:

0.0000620

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:

0.0000355

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000622

AC:

AN:

1446888

Hom.:

Cov.:

AF XY:

0.00000971

AC XY:

AN XY:

720566

show subpopulations

Gnomad4 AFR exome

AF:

0.0000608

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:

0.00000635

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.637T>A (p.F213I) alteration is located in exon 10 (coding exon 9) of the ANXA3 gene. This alteration results from a T to A substitution at nucleotide position 637, causing the phenylalanine (F) at amino acid position 213 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.22

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.10

T;T;T

Eigen

Benign

0.068

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.80

T;.;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.42

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Benign

0.26

Sift

Uncertain

0.017

D;D;D

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

0.17

B;.;.

Vest4

0.64

MVP

0.56

MPC

0.61

ClinPred

0.83

GERP RS

5.0

Varity_R

0.86

gMVP

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over