1-114679616-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3BP4_StrongBS1_SupportingBS2

The NM_000036.3(AMPD1):c.860A>T(p.Lys287Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 1,612,856 control chromosomes in the GnomAD database, including 976 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.026 ( 91 hom., cov: 32)

Exomes 𝑓: 0.032 ( 885 hom. )

Consequence

AMPD1
NM_000036.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5B:5O:1

Conservation

PhyloP100: 8.02

Publications

24 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 -8 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.005099088).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0265 (3999/151108) while in subpopulation NFE AF = 0.0344 (2325/67666). AF 95% confidence interval is 0.0332. There are 91 homozygotes in GnomAd4. There are 2075 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 91 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000036.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMPD1	NM_000036.3	MANE Select	c.860A>T	p.Lys287Ile	missense	Exon 7 of 16	NP_000027.3
	AMPD1	NM_001172626.2		c.848A>T	p.Lys283Ile	missense	Exon 6 of 15	NP_001166097.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AMPD1	ENST00000520113.7	TSL:1 MANE Select	c.860A>T	p.Lys287Ile	missense	Exon 7 of 16	ENSP00000430075.3
AMPD1	ENST00000369538.4	TSL:2	c.848A>T	p.Lys283Ile	missense	Exon 6 of 15	ENSP00000358551.4
AMPD1	ENST00000637080.1	TSL:5	n.*67A>T		non_coding_transcript_exon	Exon 5 of 14	ENSP00000489753.1

Frequencies

GnomAD3 genomes

AF:

0.0265

AC:

4000

AN:

150990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00542

Gnomad AMI

AF:

0.130

Gnomad AMR

AF:

0.0164

Gnomad ASJ

AF:

0.0235

Gnomad EAS

AF:

0.000585

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.0847

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0344

Gnomad OTH

AF:

0.0226

GnomAD2 exomes

AF:

0.0283

AC:

7112

AN:

251474

AF XY:

0.0287

show subpopulations

Gnomad AFR exome

AF:

0.00437

Gnomad AMR exome

AF:

0.0155

Gnomad ASJ exome

AF:

0.0241

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0830

Gnomad NFE exome

AF:

0.0335

Gnomad OTH exome

AF:

0.0296

GnomAD4 exome

AF:

0.0316

AC:

46263

AN:

1461748

Hom.:

885

Cov.:

AF XY:

0.0314

AC XY:

22810

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.00439

AC:

147

AN:

33480

American (AMR)

AF:

0.0159

AC:

711

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0238

AC:

622

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.0155

AC:

1337

AN:

86256

European-Finnish (FIN)

AF:

0.0803

AC:

4290

AN:

53410

Middle Eastern (MID)

AF:

0.0196

AC:

113

AN:

5766

European-Non Finnish (NFE)

AF:

0.0335

AC:

37234

AN:

1111898

Other (OTH)

AF:

0.0299

AC:

1808

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

2385

4770

7156

9541

11926

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1336

2672

4008

5344

6680

<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:

0.0265

AC:

3999

AN:

151108

Hom.:

Cov.:

AF XY:

0.0281

AC XY:

2075

AN XY:

73888

show subpopulations

African (AFR)

AF:

0.00541

AC:

222

AN:

41064

American (AMR)

AF:

0.0164

AC:

249

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.0235

AC:

AN:

3448

East Asian (EAS)

AF:

0.000586

AC:

AN:

5118

South Asian (SAS)

AF:

0.0116

AC:

AN:

4740

European-Finnish (FIN)

AF:

0.0847

AC:

894

AN:

10552

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0344

AC:

2325

AN:

67666

Other (OTH)

AF:

0.0224

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

198

397

595

794

992

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0304

Hom.:

Bravo

AF:

0.0207

TwinsUK

AF:

0.0372

AC:

138

ALSPAC

AF:

0.0353

AC:

136

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0344

AC:

296

ExAC

AF:

0.0282

AC:

3425

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0317

EpiControl

AF:

0.0287

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Muscle AMP deaminase deficiency (5)

not provided (4)

not specified (3)

AMPD1-related disorder (1)

Hypercholesterolemia, autosomal dominant, type B;C3714933:Muscle AMP deaminase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0051

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

3.8

PhyloP100

8.0

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-6.9

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.35

MPC

0.60

ClinPred

0.87

GERP RS

5.6

Varity_R

0.88

gMVP

0.75

Mutation Taster

=85/15

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over