dbSNP rs267731: ANXA9:p.Met1? (chr1-150983106-A-G) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PVS1_SupportingBS1BS2

The NM_003568.3(ANXA9):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0333 in 1,613,560 control chromosomes in the GnomAD database, including 1,105 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.025 ( 76 hom., cov: 32)

Exomes 𝑓: 0.034 ( 1029 hom. )

Consequence

ANXA9
NM_003568.3 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.80

Publications

15 publications found

Variant links:

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]

ANXA9 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 8 codons. Genomic position: 150983127. Lost 0.021 part of the original CDS.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0254 (3855/152040) while in subpopulation NFE AF = 0.0394 (2678/67964). AF 95% confidence interval is 0.0382. There are 76 homozygotes in GnomAd4. There are 1877 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 76 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANXA9	NM_003568.3 link	c.1A>G	p.Met1?	start_lost	Exon 3 of 14	ENST00000368947.9	NP_003559.2	O76027

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANXA9	ENST00000368947.9 link	c.1A>G	p.Met1?	start_lost	Exon 3 of 14	1	NM_003568.3	ENSP00000357943.4		O76027
ANXA9	ENST00000474997.1 link	n.229-232A>G		intron_variant	Intron 2 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.0254

AC:

3853

AN:

151922

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00573

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.0253

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.000388

Gnomad SAS

AF:

0.00416

Gnomad FIN

AF:

0.0357

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0394

Gnomad OTH

AF:

0.0272

GnomAD2 exomes

AF:

0.0250

AC:

6264

AN:

251000

AF XY:

0.0244

show subpopulations

Gnomad AFR exome

AF:

0.00560

Gnomad AMR exome

AF:

0.0169

Gnomad ASJ exome

AF:

0.0194

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0339

Gnomad NFE exome

AF:

0.0386

Gnomad OTH exome

AF:

0.0268

GnomAD4 exome

AF:

0.0341

AC:

49809

AN:

1461520

Hom.:

1029

Cov.:

AF XY:

0.0332

AC XY:

24124

AN XY:

727072

show subpopulations

African (AFR)

AF:

0.00517

AC:

173

AN:

33478

American (AMR)

AF:

0.0172

AC:

767

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.0181

AC:

473

AN:

26114

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00380

AC:

328

AN:

86246

European-Finnish (FIN)

AF:

0.0323

AC:

1724

AN:

53400

Middle Eastern (MID)

AF:

0.00902

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0401

AC:

44576

AN:

1111750

Other (OTH)

AF:

0.0284

AC:

1715

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

2247

4494

6741

8988

11235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1630

3260

4890

6520

8150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0254

AC:

3855

AN:

152040

Hom.:

Cov.:

AF XY:

0.0253

AC XY:

1877

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.00571

AC:

237

AN:

41476

American (AMR)

AF:

0.0253

AC:

387

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

AN:

3468

East Asian (EAS)

AF:

0.000389

AC:

AN:

5138

South Asian (SAS)

AF:

0.00417

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.0357

AC:

378

AN:

10576

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0394

AC:

2678

AN:

67964

Other (OTH)

AF:

0.0274

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

192

383

575

766

958

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0335

Hom.:

324

Bravo

AF:

0.0238

TwinsUK

AF:

0.0380

AC:

141

ALSPAC

AF:

0.0348

AC:

134

ESP6500AA

AF:

0.00704

AC:

ESP6500EA

AF:

0.0381

AC:

328

ExAC

AF:

0.0246

AC:

2984

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0371

EpiControl

AF:

0.0385

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0022

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.91

PhyloP100

2.8

PROVEAN

Benign

-0.48

REVEL

Benign

0.15

Sift

Benign

0.049

Sift4G

Pathogenic

0.0

Polyphen

0.0010

Vest4

0.28

ClinPred

0.020

GERP RS

3.9

Varity_R

0.28

gMVP

0.56

Mutation Taster

=109/91

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over