4-78586315-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005139.3(ANXA3):c.368G>A(p.Arg123Lys) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ANXA3 NM_005139.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041439325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANXA3	NM_005139.3	c.368G>A	p.Arg123Lys	missense_variant	6/13	ENST00000264908.11
ANXA3	XM_047450154.1	c.368G>A	p.Arg123Lys	missense_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANXA3	ENST00000264908.11	c.368G>A	p.Arg123Lys	missense_variant	6/13	1	NM_005139.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Oct 20, 2023

The c.368G>A (p.R123K) alteration is located in exon 6 (coding exon 5) of the ANXA3 gene. This alteration results from a G to A substitution at nucleotide position 368, causing the arginine (R) at amino acid position 123 to be replaced by a lysine (K). 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	0.099
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	15
Dann	Benign	0.95
DEOGEN2	Benign	0.017	T;T;T;T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.59	T;.;T;T;T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.041	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.89	N;.;.;.;.
MutationTaster	Benign	0.84	N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.46	N;N;N;N;N
REVEL	Benign	0.028
Sift	Benign	0.43	T;T;T;T;T
Sift4G	Benign	0.79	T;T;T;T;T
Polyphen		0.0	B;.;.;.;.
Vest4		0.13
MutPred		0.34		Gain of methylation at R123 (P = 0.0168);.;.;Gain of methylation at R123 (P = 0.0168);Gain of methylation at R123 (P = 0.0168);
MVP		0.23
MPC		0.11
ClinPred		0.17	T
GERP RS		2.6
Varity_R		0.14
gMVP		0.16

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: chr4-79507469;