4-78573220-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005139.3(ANXA3):c.56G>A(p.Ser19Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,613,618 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S19R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (55 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (60 hom.)
• Consequence: ANXA3 NM_005139.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0640

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025430024).
• BP6: Variant 4-78573220-G-A is Benign according to our data. Variant chr4-78573220-G-A is described in ClinVar as [Benign]. Clinvar id is 773707.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANXA3	NM_005139.3	c.56G>A	p.Ser19Asn	missense_variant	3/13	ENST00000264908.11
ANXA3	XM_047450154.1	c.56G>A	p.Ser19Asn	missense_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANXA3	ENST00000264908.11	c.56G>A	p.Ser19Asn	missense_variant	3/13	1	NM_005139.3	P1

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2113 AN: 152154 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.0478

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00377 AC: 946 AN: 251050 Hom.: 25 AF XY: 0.00282 AC XY: 382 AN XY: 135674

Gnomad AFR exome AF: 0.0503

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00150 AC: 2190 AN: 1461346 Hom.: 60 Cov.: 30 AF XY: 0.00135 AC XY: 984 AN XY: 726978

Gnomad4 AFR exome AF: 0.0523

Gnomad4 AMR exome AF: 0.00259

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000693

Gnomad4 OTH exome AF: 0.00335

GnomAD4 genome AF: 0.0140 AC: 2130 AN: 152272 Hom.: 55 Cov.: 32 AF XY: 0.0132 AC XY: 980 AN XY: 74464

Gnomad4 AFR AF: 0.0481

Gnomad4 AMR AF: 0.00589

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00285 Hom.: 11

Bravo AF: 0.0160

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0465 AC: 205

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00430 AC: 522

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.28
Dann	Benign	0.14
DEOGEN2	Benign	0.019	T;.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.73	T;T;T;T
MetaRNN	Benign	0.0025	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.33	N;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.1	N;N;N;N
REVEL	Benign	0.056
Sift	Benign	0.88	T;T;T;T
Sift4G	Benign	0.88	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.11
MVP		0.19
MPC		0.097
ClinPred		0.0038	T
GERP RS		-0.89
Varity_R		0.060
gMVP		0.23

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: rs5951; hg19: chr4-79494374;