1-150983106-A-G

Variant names:

• chr1-150983106-A-G
• rs267731
• NM_003568.3:c.1A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PVS1_Supporting BS1 BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.80
• Publications: 15 publications found

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]

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003568.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANXA9	NM_003568.3	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 3 of 14	NP_003559.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANXA9	ENST00000368947.9	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 3 of 14	ENSP00000357943.4
	ANXA9	ENST00000474997.1	TSL:3	n.229-232A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3853 AN: 151922 Hom.: 76 Cov.: 32

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

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.: 31 AF XY: 0.0332 AC XY: 24124 AN XY: 727072

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: 1 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: 52 AN: 5764

European-Non Finnish (NFE) AF: 0.0401 AC: 44576 AN: 1111750

Other (OTH) AF: 0.0284 AC: 1715 AN: 60372

GnomAD4 genome AF: 0.0254 AC: 3855 AN: 152040 Hom.: 76 Cov.: 32 AF XY: 0.0253 AC XY: 1877 AN XY: 74324

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: 57 AN: 3468

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5138

South Asian (SAS) AF: 0.00417 AC: 20 AN: 4800

European-Finnish (FIN) AF: 0.0357 AC: 378 AN: 10576

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0394 AC: 2678 AN: 67964

Other (OTH) AF: 0.0274 AC: 58 AN: 2114

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: 31

ESP6500EA AF: 0.0381 AC: 328

ExAC AF: 0.0246 AC: 2984

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0371

EpiControl AF: 0.0385

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.91	T
PhyloP100		2.8
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.15
Sift	Benign	0.049	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.28
ClinPred		0.020	T
GERP RS		3.9
Varity_R		0.28
gMVP		0.56
Mutation Taster		=109/91	polymorphism (auto)

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

Other links and lift over

dbSNP: rs267731; hg19: chr1-150955582;