rs61752479

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

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).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

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

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/exons	MANE	Protein	UniProt
AMPD1	NM_000036.3 linkuse as main transcript	c.143C>T	p.Pro48Leu	missense_variant	3/16	ENST00000520113.7	NP_000027.3
AMPD1	NM_001172626.2 linkuse as main transcript	c.131C>T	p.Pro44Leu	missense_variant	2/15		NP_001166097.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMPD1	ENST00000520113.7 linkuse as main transcript	c.143C>T	p.Pro48Leu	missense_variant	3/16	1	NM_000036.3	ENSP00000430075	P4	P23109-1
AMPD1	ENST00000369538.4 linkuse as main transcript	c.131C>T	p.Pro44Leu	missense_variant	2/15	2		ENSP00000358551	A1	P23109-2
AMPD1	ENST00000637080.1 linkuse as main transcript	c.146C>T	p.Pro49Leu	missense_variant, NMD_transcript_variant	2/14	5		ENSP00000489753

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

GnomAD3 exomes

AF:

0.0876

AC:

22018

AN:

251420

Hom.:

1331

AF XY:

0.0888

AC XY:

12065

AN XY:

135876

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 SAS exome

AF:

0.0355

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

Gnomad4 AFR exome

AF:

0.0179

Gnomad4 AMR exome

AF:

0.0524

Gnomad4 ASJ exome

AF:

0.0794

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0357

Gnomad4 FIN exome

AF:

0.119

Gnomad4 NFE exome

AF:

0.132

Gnomad4 OTH exome

AF:

0.103

GnomAD4 genome

AF:

0.0864

AC:

13146

AN:

152144

Hom.:

781

Cov.:

AF XY:

0.0837

AC XY:

6223

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0220

Gnomad4 AMR

AF:

0.0726

Gnomad4 ASJ

AF:

0.0735

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0278

Gnomad4 FIN

AF:

0.119

Gnomad4 NFE

AF:

0.134

Gnomad4 OTH

AF:

0.0825

Alfa

AF:

0.116

Hom.:

1867

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

other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 07, 2018	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 1631143, 33250842, 21228398, 20981092) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Muscle AMP deaminase deficiency

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	Jan 06, 2021	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] -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 06, 2020	- -

AMPD1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2023

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

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;.

MutationTaster

Benign

5.7e-12

P;P;P

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

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

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