Genetic Variant ANXA8L1:p.Lys125Asn (chr10-46383509-G-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001098845.3(ANXA8L1):c.375G>T(p.Lys125Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 9)

Exomes 𝑓: 0.0000091 ( 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: 1.01

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.045312136).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANXA8L1	NM_001098845.3 link	c.375G>T	p.Lys125Asn	missense_variant	Exon 5 of 12	ENST00000619162.5	NP_001092315.2	P13928Q5VT79-1
ANXA8L1	NM_001278924.2 link	c.435+817G>T		intron_variant	Intron 4 of 8		NP_001265853.1	Q5VT79-2
ANXA8L1	NM_001278923.2 link	c.321+817G>T		intron_variant	Intron 4 of 9		NP_001265852.1	B4DTF2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANXA8L1	ENST00000619162.5 link	c.375G>T	p.Lys125Asn	missense_variant	Exon 5 of 12	1	NM_001098845.3	ENSP00000480221.1		Q5VT79-1

Frequencies

GnomAD3 genomes

AF:

0.0000144

AC:

AN:

69222

Hom.:

Cov.:

show subpopulations

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:

0.0000284

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000667

AC:

AN:

149840

AF XY:

0.0000128

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000166

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000909

AC:

AN:

879616

Hom.:

Cov.:

AF XY:

0.00000672

AC XY:

AN XY:

446408

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

19774

American (AMR)

AF:

0.00

AC:

AN:

31856

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18092

East Asian (EAS)

AF:

0.00

AC:

AN:

35226

South Asian (SAS)

AF:

0.00

AC:

AN:

63184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2894

European-Non Finnish (NFE)

AF:

0.0000129

AC:

AN:

622442

Other (OTH)

AF:

0.00

AC:

AN:

39716

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000039), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.356

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000144

AC:

AN:

69222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32780

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

14820

American (AMR)

AF:

0.00

AC:

AN:

6216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1906

East Asian (EAS)

AF:

0.00

AC:

AN:

2994

South Asian (SAS)

AF:

0.00

AC:

AN:

1350

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5224

Middle Eastern (MID)

AF:

0.00

AC:

AN:

168

European-Non Finnish (NFE)

AF:

0.0000284

AC:

AN:

35254

Other (OTH)

AF:

0.00

AC:

AN:

794

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000260

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 21, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.375G>T (p.K125N) alteration is located in exon 5 (coding exon 5) of the ANXA8L2 gene. This alteration results from a G to T substitution at nucleotide position 375, causing the lysine (K) at amino acid position 125 to be replaced by an asparagine (N). 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

Uncertain

0.39

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0067

T;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.016

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.0079

MetaRNN

Benign

0.045

T;T;T

MetaSVM

Benign

-0.95

PhyloP100

1.0

Sift4G

Benign

1.0

T;T;T

Polyphen

0.023

.;.;B

Vest4

0.31

MutPred

0.51

.;.;Loss of methylation at K125 (P = 0.0251);

MVP

0.040

ClinPred

0.87

GERP RS

0.059

Varity_R

0.26

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over