Genetic Variant NM_003568.3:c.749A>C (chr1-150988142-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003568.3(ANXA9):c.749A>C(p.Gln250Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.00026 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ANXA9
NM_003568.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0490

Variant links:

Genes affected

ANXA9 (HGNC:547): (annexin A9) The annexins are a family of calcium-dependent phospholipid-binding proteins. Members of the annexin family contain 4 internal repeat domains, each of which includes a type II calcium-binding site. The calcium-binding sites are required for annexins to aggregate and cooperatively bind anionic phospholipids and extracellular matrix proteins. This gene encodes a divergent member of the annexin protein family in which all four homologous type II calcium-binding sites in the conserved tetrad core contain amino acid substitutions that ablate their function. However, structural analysis suggests that the conserved putative ion channel formed by the tetrad core is intact. [provided by RefSeq, Jul 2008]

ANXA9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20874849).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANXA9	NM_003568.3 link	c.749A>C	p.Gln250Pro	missense_variant	Exon 11 of 14	ENST00000368947.9	NP_003559.2	O76027

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANXA9	ENST00000368947.9 link	c.749A>C	p.Gln250Pro	missense_variant	Exon 11 of 14	1	NM_003568.3	ENSP00000357943.4		O76027

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000255

AC:

373

AN:

1461000

Hom.:

Cov.:

AF XY:

0.000241

AC XY:

175

AN XY:

726832

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000309

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.749A>C (p.Q250P) alteration is located in exon 11 (coding exon 9) of the ANXA9 gene. This alteration results from a A to C substitution at nucleotide position 749, causing the glutamine (Q) at amino acid position 250 to be replaced by a proline (P). 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

Uncertain

0.36

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.59

DEOGEN2

Benign

0.0052

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.57

M_CAP

Benign

0.0035

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.96

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.8

REVEL

Benign

0.089

Sift

Benign

0.060

Sift4G

Uncertain

0.036

Polyphen

0.43

Vest4

0.48

MutPred

0.50

Gain of disorder (P = 0.2497);

MVP

0.21

MPC

0.063

ClinPred

0.13

GERP RS

-3.1

Varity_R

0.29

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over