11-10487356-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001025389.2(AMPD3):c.931G>T(p.Val311Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0082 in 1,614,054 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V311M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0068 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0083 ( 63 hom. )

Consequence

AMPD3
NM_001025389.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 5.91

Publications

17 publications found

Variant links:

Genes affected

AMPD3 (HGNC:470): (adenosine monophosphate deaminase 3) This gene encodes a member of the AMP deaminase gene family. The encoded protein is a highly regulated enzyme that catalyzes the hydrolytic deamination of adenosine monophosphate to inosine monophosphate, a branch point in the adenylate catabolic pathway. This gene encodes the erythrocyte (E) isoforms, whereas other family members encode isoforms that predominate in muscle (M) and liver (L) cells. Mutations in this gene lead to the clinically asymptomatic, autosomal recessive condition erythrocyte AMP deaminase deficiency. Alternatively spliced transcript variants encoding different isoforms of this gene have been described. [provided by RefSeq, Jul 2008]

AMPD3 Gene-Disease associations (from GenCC):

adenosine monophosphate deaminase deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

AMPD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015119016).

BP6

Variant 11-10487356-G-T is Benign according to our data. Variant chr11-10487356-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166685.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMPD3	NM_001025389.2 link	c.931G>T	p.Val311Leu	missense_variant	Exon 6 of 15	ENST00000396553.7	NP_001020560.1	Q01432-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMPD3	ENST00000396553.7 link	c.931G>T	p.Val311Leu	missense_variant	Exon 6 of 15	1	NM_001025389.2	ENSP00000379801.2		Q01432-1

Frequencies

GnomAD3 genomes

AF:

0.00681

AC:

1036

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.0116

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0105

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00672

AC:

1689

AN:

251464

AF XY:

0.00661

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.00280

Gnomad ASJ exome

AF:

0.00605

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00924

Gnomad NFE exome

AF:

0.0104

Gnomad OTH exome

AF:

0.00603

GnomAD4 exome

AF:

0.00835

AC:

12200

AN:

1461764

Hom.:

Cov.:

AF XY:

0.00818

AC XY:

5948

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00117

AC:

AN:

33474

American (AMR)

AF:

0.00309

AC:

138

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00505

AC:

132

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00290

AC:

250

AN:

86258

European-Finnish (FIN)

AF:

0.0101

AC:

540

AN:

53402

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00964

AC:

10719

AN:

1111918

Other (OTH)

AF:

0.00614

AC:

371

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

707

1414

2122

2829

3536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

374

748

1122

1496

1870

<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:

0.00680

AC:

1036

AN:

152290

Hom.:

Cov.:

AF XY:

0.00657

AC XY:

489

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00200

AC:

AN:

41574

American (AMR)

AF:

0.00490

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00404

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00373

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0116

AC:

123

AN:

10610

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0105

AC:

713

AN:

68022

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

114

171

228

285

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00856

Hom.:

Bravo

AF:

0.00557

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0121

AC:

104

ExAC

AF:

0.00733

AC:

890

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00774

EpiControl

AF:

0.00782

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Erythrocyte AMP deaminase deficiency

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:1

Jan 27, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

AMPD3-related disorder

Benign:1

Jul 13, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

May 30, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

.;.;D;.;D

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;.;D;D

MetaRNN

Benign

0.015

T;T;T;T;T

MetaSVM

Uncertain

0.38

MutationAssessor

Uncertain

2.5

.;.;M;.;M

PhyloP100

5.9

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.1

N;N;N;N;N

REVEL

Pathogenic

0.77

Sift

Uncertain

0.014

D;D;D;D;D

Sift4G

Uncertain

0.017

D;T;T;T;T

Polyphen

0.95

.;.;P;.;P

Vest4

0.78

MutPred

0.84

.;.;Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);

MVP

0.94

MPC

0.96

ClinPred

0.015

GERP RS

5.2

Varity_R

0.28

gMVP

0.67

Mutation Taster

=46/31

polymorphism

(source)

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

Publications

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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