4-78597346-A-C

Variant summary

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

The NM_005139.3(ANXA3):c.662A>C(p.Gln221Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANXA3 NM_005139.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.22

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]

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=0.20627546).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANXA3	NM_005139.3	c.662A>C	p.Gln221Pro	missense_variant	10/13	ENST00000264908.11
ANXA3	XM_047450154.1	c.662A>C	p.Gln221Pro	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANXA3	ENST00000264908.11	c.662A>C	p.Gln221Pro	missense_variant	10/13	1	NM_005139.3	P1
ANXA3	ENST00000503570.6	c.545A>C	p.Gln182Pro	missense_variant	11/14	5
ANXA3	ENST00000512884.5	c.545A>C	p.Gln182Pro	missense_variant	9/12	5
ANXA3	ENST00000505805.1	n.274A>C		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

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

Feb 06, 2023

The c.662A>C (p.Q221P) alteration is located in exon 10 (coding exon 9) of the ANXA3 gene. This alteration results from a A to C substitution at nucleotide position 662, causing the glutamine (Q) at amino acid position 221 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	Benign	0.24
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	25
Dann	Benign	0.96
DEOGEN2	Benign	0.052	T;T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.065
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D;.;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;.
MutationTaster	Benign	0.66	D;D;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0090	D;T;T
Sift4G	Uncertain	0.047	D;T;T
Polyphen		0.028	B;.;.
Vest4		0.51
MutPred		0.51		Loss of stability (P = 0.0718);.;.;
MVP		0.30
MPC		0.16
ClinPred		0.59	D
GERP RS		5.0
Varity_R		0.69
gMVP		0.76

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.

Other links and lift over

hg19: chr4-79518500;