rs146496147

Variant names:

• chr4-121669691-C-G
• rs146496147
• NM_001154.4:c.814G>C

Your query was ambiguous. Multiple possible variants found:

• chr4-121669691-C-G
• chr4-121669691-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001154.4(ANXA5):​c.814G>C​(p.Val272Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V272G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ANXA5 NM_001154.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.963
• Publications: 1 publications found

Genes affected

ANXA5 (HGNC:543): (annexin A5) The Annexin 5 gene spans 29 kb containing 13 exons, and encodes a single transcript of approximately 1.6 kb and a protein product with a molecular weight of about 35 kDa.The protein encoded by this gene belongs to the annexin family of calcium-dependent phospholipid binding proteins some of which have been implicated in membrane-related events along exocytotic and endocytotic pathways. Annexin 5 is a phospholipase A2 and protein kinase C inhibitory protein with calcium channel activity and a potential role in cellular signal transduction, inflammation, growth and differentiation. Annexin 5 has also been described as placental anticoagulant protein I, vascular anticoagulant-alpha, endonexin II, lipocortin V, placental protein 4 and anchorin CII. Polymorphisms in this gene have been implicated in various obstetric complications. [provided by RefSeq, Dec 2019]

ANXA5 Gene-Disease associations (from GenCC):

• pregnancy loss, recurrent, susceptibility to, 3

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34715778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANXA5	NM_001154.4	c.814G>C	p.Val272Leu	missense_variant	Exon 12 of 13	ENST00000296511.10	NP_001145.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANXA5	ENST00000296511.10	c.814G>C	p.Val272Leu	missense_variant	Exon 12 of 13	1	NM_001154.4	ENSP00000296511.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460834 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726734

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111288

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.048
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;.
PhyloP100		0.96
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.099
Sift	Benign	0.054	T;D;D
Sift4G	Benign	0.069	T;D;D
Polyphen		0.011	B;B;B
Vest4		0.59
MutPred		0.69		Loss of catalytic residue at S275 (P = 0.1388);.;.;
MVP		0.34
MPC		0.23
ClinPred		0.46	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.65
Mutation Taster		=78/22	polymorphism

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: rs146496147; hg19: chr4-122590846;