rs61752479

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_000036.3(AMPD1):c.143C>T(p.Pro48Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,613,946 control chromosomes in the GnomAD database, including 11,561 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars). Synonymous variant affecting the same amino acid position (i.e. P48P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.086 ( 781 hom., cov: 32)

Exomes 𝑓: 0.11 ( 10780 hom. )

Consequence

AMPD1
NM_000036.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications U:2B:5O:1

Conservation

PhyloP100: 9.35

Publications

27 publications found

Variant links:

Genes affected

AMPD1 (HGNC:468): (adenosine monophosphate deaminase 1) Adenosine monophosphate deaminase 1 catalyzes the deamination of AMP to IMP in skeletal muscle and plays an important role in the purine nucleotide cycle. Two other genes have been identified, AMPD2 and AMPD3, for the liver- and erythocyte-specific isoforms, respectively. Deficiency of the muscle-specific enzyme is apparently a common cause of exercise-induced myopathy and probably the most common cause of metabolic myopathy in the human. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene.[provided by RefSeq, Feb 2010]

AMPD1 Gene-Disease associations (from GenCC):

myopathy due to myoadenylate deaminase deficiency
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
adenosine monophosphate deaminase deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

AMPD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030060112).

BP6

Variant 1-114688633-G-A is Benign according to our data. Variant chr1-114688633-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity|other. ClinVar VariationId is 50897.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMPD1	NM_000036.3 link	c.143C>T	p.Pro48Leu	missense_variant	Exon 3 of 16	ENST00000520113.7	NP_000027.3	P23109-1
AMPD1	NM_001172626.2 link	c.131C>T	p.Pro44Leu	missense_variant	Exon 2 of 15		NP_001166097.2	P23109-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AMPD1	ENST00000520113.7 link	c.143C>T	p.Pro48Leu	missense_variant	Exon 3 of 16	1	NM_000036.3	ENSP00000430075.3	P23109-1
AMPD1	ENST00000369538.4 link	c.131C>T	p.Pro44Leu	missense_variant	Exon 2 of 15	2		ENSP00000358551.4	P23109-2
AMPD1	ENST00000637080.1 link	n.146C>T		non_coding_transcript_exon_variant	Exon 2 of 14	5		ENSP00000489753.1	A0A1B0GTL6

Frequencies

GnomAD3 genomes

AF:

0.0865

AC:

13148

AN:

152026

Hom.:

781

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0221

Gnomad AMI

AF:

0.135

Gnomad AMR

AF:

0.0727

Gnomad ASJ

AF:

0.0735

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0282

Gnomad FIN

AF:

0.119

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.134

Gnomad OTH

AF:

0.0839

GnomAD2 exomes

AF:

0.0876

AC:

22018

AN:

251420

AF XY:

0.0888

show subpopulations

Gnomad AFR exome

AF:

0.0202

Gnomad AMR exome

AF:

0.0509

Gnomad ASJ exome

AF:

0.0768

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.116

Gnomad NFE exome

AF:

0.132

Gnomad OTH exome

AF:

0.0932

GnomAD4 exome

AF:

0.115

AC:

167963

AN:

1461802

Hom.:

10780

Cov.:

AF XY:

0.113

AC XY:

82083

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.0179

AC:

598

AN:

33480

American (AMR)

AF:

0.0524

AC:

2342

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0794

AC:

2076

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0357

AC:

3079

AN:

86258

European-Finnish (FIN)

AF:

0.119

AC:

6331

AN:

53418

Middle Eastern (MID)

AF:

0.0700

AC:

404

AN:

5768

European-Non Finnish (NFE)

AF:

0.132

AC:

146903

AN:

1111922

Other (OTH)

AF:

0.103

AC:

6224

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

8735

17469

26204

34938

43673

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5040

10080

15120

20160

25200

<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:

0.0864

AC:

13146

AN:

152144

Hom.:

781

Cov.:

AF XY:

0.0837

AC XY:

6223

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0220

AC:

915

AN:

41500

American (AMR)

AF:

0.0726

AC:

1110

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0735

AC:

255

AN:

3470

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.0278

AC:

134

AN:

4822

European-Finnish (FIN)

AF:

0.119

AC:

1258

AN:

10570

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.134

AC:

9144

AN:

68000

Other (OTH)

AF:

0.0825

AC:

174

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

607

1215

1822

2430

3037

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

150

300

450

600

750

<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:

0.113

Hom.:

3902

Bravo

AF:

0.0799

TwinsUK

AF:

0.144

AC:

533

ALSPAC

AF:

0.127

AC:

491

ESP6500AA

AF:

0.0234

AC:

103

ESP6500EA

AF:

0.133

AC:

1144

ExAC

AF:

0.0884

AC:

10728

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.125

EpiControl

AF:

0.128

ClinVar

Significance: Conflicting classifications of pathogenicity; other

Submissions summary: Uncertain:2Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2Other:1

Feb 07, 2018

Eurofins Ntd Llc (ga)

Significance:other

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 1631143, 33250842, 21228398, 20981092) -

Jun 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Muscle AMP deaminase deficiency

Uncertain:1Benign:2

Jan 06, 2021

Clinical Genomics Laboratory, Stanford Medicine

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The p.Pro81Leu variant in the AMPD1 gene has been previously reported in 11 unrelated individuals with reported AMPD deficiency (Morisaki et al., 1992). Of note, all individuals were homozygous for this variant as well as the p.Gln45* variant. The highest allele frequency of the p.Pro81Leu variant was identified in the European population at 17,214/129,128 chromosomes (13.33%) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools predict that the p.Pro81Leu variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Pro81Leu variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PP3] -

Jan 06, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

AMPD1-related disorder

Benign:1

Dec 01, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

T;T

MetaRNN

Benign

0.0030

T;T

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.4

M;.

PhyloP100

9.3

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Uncertain

0.51

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.012

D;D

Vest4

0.32

MPC

0.46

ClinPred

0.028

GERP RS

5.6

Varity_R

0.66

gMVP

0.69

Mutation Taster

=92/8

polymorphism (auto)

(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