Genetic Variant NM_001098845.3:c.524A>G (chr10-46384805-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001098845.3(ANXA8L1):c.524A>G(p.Asp175Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 24)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ANXA8L1
NM_001098845.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.97

Variant links:

Genes affected

ANXA8L1 (HGNC:23334): (annexin A8 like 1) This gene encodes a member of the annexin family of evolutionarily conserved Ca2+ and phospholipid binding proteins. The encoded protein may function as an an anticoagulant that indirectly inhibits the thromboplastin-specific complex. Overexpression of this gene has been associated with acute myelocytic leukemia. A highly similar duplicated copy of this gene is found in close proximity on the long arm of chromosome 10. [provided by RefSeq, Apr 2014]

ANXA8L1 links:

ENSG00000285402 (HGNC:):

ENSG00000285402 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANXA8L1	NM_001098845.3 link	c.524A>G	p.Asp175Gly	missense_variant	Exon 7 of 12	ENST00000619162.5	NP_001092315.2	P13928Q5VT79-1
ANXA8L1	NM_001278924.2 link	c.467A>G	p.Asp156Gly	missense_variant	Exon 5 of 9		NP_001265853.1	Q5VT79-2
ANXA8L1	NM_001278923.2 link	c.353A>G	p.Asp118Gly	missense_variant	Exon 5 of 10		NP_001265852.1	B4DTF2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANXA8L1	ENST00000619162.5 link	c.524A>G	p.Asp175Gly	missense_variant	Exon 7 of 12	1	NM_001098845.3	ENSP00000480221.1		Q5VT79-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151476

Hom.:

Cov.:

FAILED QC

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461514

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

151476

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73964

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000936

Hom.:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.524A>G (p.D175G) alteration is located in exon 7 (coding exon 7) of the ANXA8L2 gene. This alteration results from a A to G substitution at nucleotide position 524, causing the aspartic acid (D) at amino acid position 175 to be replaced by a glycine (G). 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

Pathogenic

0.69

BayesDel_addAF

Benign

0.010

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;.;.;T;.

Eigen

Uncertain

0.41

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.77

T;D;D;T;D

M_CAP

Benign

0.045

MetaRNN

Pathogenic

0.83

D;D;D;D;D

MetaSVM

Benign

-0.67

Sift4G

Uncertain

0.0060

D;D;D;D;D

Polyphen

1.0, 0.79, 1.0

.;.;D;P;D

Vest4

0.76

MutPred

0.59

.;.;.;Loss of stability (P = 0.0518);.;

MVP

0.29

ClinPred

0.96

GERP RS

1.8

Varity_R

0.11

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over