4-78595815-A-G

Variant summary

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

The NM_005139.3(ANXA3):c.562A>G(p.Asn188Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,610,658 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: ANXA3 NM_005139.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.37

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=0.085742295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANXA3	NM_005139.3	c.562A>G	p.Asn188Asp	missense_variant	9/13	ENST00000264908.11
ANXA3	XM_047450154.1	c.562A>G	p.Asn188Asp	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANXA3	ENST00000264908.11	c.562A>G	p.Asn188Asp	missense_variant	9/13	1	NM_005139.3	P1
ANXA3	ENST00000503570.6	c.445A>G	p.Asn149Asp	missense_variant	10/14	5
ANXA3	ENST00000512884.5	c.445A>G	p.Asn149Asp	missense_variant	8/12	5
ANXA3	ENST00000512542.5	c.94A>G	p.Asn32Asp	missense_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000151 AC: 38 AN: 250968 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135638

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000243 AC: 354 AN: 1458302 Hom.: 1 Cov.: 28 AF XY: 0.000238 AC XY: 173 AN XY: 725740

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000287

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74508

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000289 Hom.: 0

Bravo AF: 0.000170

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000164

EpiControl AF: 0.000356

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

Jun 24, 2022

The c.562A>G (p.N188D) alteration is located in exon 9 (coding exon 8) of the ANXA3 gene. This alteration results from a A to G substitution at nucleotide position 562, causing the asparagine (N) at amino acid position 188 to be replaced by an aspartic acid (D). 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	0.12
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.60
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.042	T;T;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;.;T;D
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.086	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.24	N;.;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Benign	0.042
Sift	Benign	0.27	T;T;T;T
Sift4G	Benign	0.29	T;T;T;T
Polyphen		0.0080	B;.;.;.
Vest4		0.25
MVP		0.31
MPC		0.13
ClinPred		0.19	T
GERP RS		5.2
Varity_R		0.41
gMVP		0.31

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

Other links and lift over

dbSNP: rs199594648; hg19: chr4-79516969;