1-150986624-G-C

Position:

• chr1-150986624-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003568.3(ANXA9):​c.575G>C​(p.Gly192Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000269 in 1,451,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.000027 (0 hom.)
• Consequence: ANXA9 NM_003568.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.38

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20015004).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANXA9	NM_003568.3	c.575G>C	p.Gly192Ala	missense_variant	9/14	ENST00000368947.9	NP_003559.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANXA9	ENST00000368947.9	c.575G>C	p.Gly192Ala	missense_variant	9/14	1	NM_003568.3	ENSP00000357943	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000269 AC: 39 AN: 1451696 Hom.: 0 Cov.: 31 AF XY: 0.0000235 AC XY: 17 AN XY: 722344

Gnomad4 AFR exome AF: 0.00

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: 0.0000352

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2023

The c.575G>C (p.G192A) alteration is located in exon 9 (coding exon 7) of the ANXA9 gene. This alteration results from a G to C substitution at nucleotide position 575, causing the glycine (G) at amino acid position 192 to be replaced by an alanine (A). 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	Benign	0.19
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0054	T
Eigen	Benign	0.050
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.085
Sift	Uncertain	0.020	D
Sift4G	Benign	0.093	T
Polyphen		0.67	P
Vest4		0.35
MVP		0.29
MPC		0.21
ClinPred		0.55	D
GERP RS		4.1
Varity_R		0.13
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1353704903; hg19: chr1-150959100;