4-78579092-G-T

Variant names:

• chr4-78579092-G-T
• rs770067653
• NM_005139.3:c.169G>T

Variant summary

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

The NM_005139.3(ANXA3):​c.169G>T​(p.Val57Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANXA3 NM_005139.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24
• Publications: 0 publications found

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

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=0.26974943).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANXA3	NM_005139.3	c.169G>T	p.Val57Phe	missense_variant	Exon 4 of 13	ENST00000264908.11	NP_005130.1
ANXA3	XM_047450154.1	c.169G>T	p.Val57Phe	missense_variant	Exon 4 of 11		XP_047306110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANXA3	ENST00000264908.11	c.169G>T	p.Val57Phe	missense_variant	Exon 4 of 13	1	NM_005139.3	ENSP00000264908.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.169G>T (p.V57F) alteration is located in exon 4 (coding exon 3) of the ANXA3 gene. This alteration results from a G to T substitution at nucleotide position 169, causing the valine (V) at amino acid position 57 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.038	T;T;T;.;T;.
Eigen	Benign	0.086
Eigen_PC	Benign	-0.012
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.89	D;.;D;T;D;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.27	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;.;.;.;.
PhyloP100		2.2
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.12	T;T;T;D;D;D
Sift4G	Uncertain	0.051	T;T;T;T;D;T
Polyphen		0.91	P;.;.;.;.;.
Vest4		0.47
MutPred		0.54		Gain of methylation at K58 (P = 0.1648);.;.;Gain of methylation at K58 (P = 0.1648);Gain of methylation at K58 (P = 0.1648);Gain of methylation at K58 (P = 0.1648);
MVP		0.54
MPC		0.54
ClinPred		0.79	D
GERP RS		5.4
Varity_R		0.49
gMVP		0.56
Mutation Taster		=66/34	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: rs770067653; hg19: chr4-79500246;