1-150986602-G-A

Variant names:

• chr1-150986602-G-A
• rs200423517
• NM_003568.3:c.553G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003568.3(ANXA9):​c.553G>A​(p.Gly185Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000498 in 1,607,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ANXA9 NM_003568.3 missense, splice_region
• Scores: Splicing: ADA: 0.9953
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.01
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANXA9	NM_003568.3	MANE Select	c.553G>A	p.Gly185Arg	missense splice_region	Exon 9 of 14	NP_003559.2	O76027

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANXA9	ENST00000368947.9	TSL:1 MANE Select	c.553G>A	p.Gly185Arg	missense splice_region	Exon 9 of 14	ENSP00000357943.4	O76027
	ANXA9	ENST00000887888.1		c.553G>A	p.Gly185Arg	missense splice_region	Exon 10 of 15	ENSP00000557947.1
	ANXA9	ENST00000887895.1		c.553G>A	p.Gly185Arg	missense splice_region	Exon 8 of 13	ENSP00000557954.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1455362 Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 724184

African (AFR) AF: 0.00 AC: 0 AN: 32956

American (AMR) AF: 0.00 AC: 0 AN: 42232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25766

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85268

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5730

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110214

Other (OTH) AF: 0.00 AC: 0 AN: 60146

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.083	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0079	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		5.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.024	D
Polyphen		0.98	D
Vest4		0.86
MutPred		0.61		Gain of solvent accessibility (P = 0.0456)
MVP		0.51
MPC		0.35
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.64
gMVP		0.62
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200423517; hg19: chr1-150959078;