rs35859650

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PS3PP3BP4_Moderate

The NM_000036.3(AMPD1):c.1162C>T(p.Arg388Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000369 in 1,613,898 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000617307: Published functional studies demonstrate a damaging effect" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R388Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

AMPD1
NM_000036.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.85

Publications

7 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: Uncertain_significance. The variant received 3 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000617307: Published functional studies demonstrate a damaging effect; specifically, expression studies of this variant form of AMPD1 in prokaryotic cells demonstrated undetectable enzyme activity despite normal quantities of AMPD1 peptides, as compared with controls (PMID: 11102975)

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, Dann, M_CAP, MutationAssessor, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.07670745).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMPD1	NM_000036.3	MANE Select	c.1162C>T	p.Arg388Trp	missense	Exon 9 of 16	NP_000027.3	P23109-1
	AMPD1	NM_001172626.2		c.1150C>T	p.Arg384Trp	missense	Exon 8 of 15	NP_001166097.2	P23109-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AMPD1	ENST00000520113.7	TSL:1 MANE Select	c.1162C>T	p.Arg388Trp	missense	Exon 9 of 16	ENSP00000430075.3	P23109-1
AMPD1	ENST00000369538.4	TSL:2	c.1150C>T	p.Arg384Trp	missense	Exon 8 of 15	ENSP00000358551.4	P23109-2
AMPD1	ENST00000637080.1	TSL:5	n.*369C>T		non_coding_transcript_exon	Exon 7 of 14	ENSP00000489753.1	A0A1B0GTL6

Frequencies

GnomAD3 genomes

AF:

0.00192

AC:

292

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00669

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000394

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000565

AC:

142

AN:

251462

AF XY:

0.000397

show subpopulations

Gnomad AFR exome

AF:

0.00726

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000207

AC:

303

AN:

1461782

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

123

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.00627

AC:

210

AN:

33480

American (AMR)

AF:

0.000358

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.000202

AC:

AN:

39698

South Asian (SAS)

AF:

0.000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

1111930

Other (OTH)

AF:

0.000497

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00193

AC:

293

AN:

152116

Hom.:

Cov.:

AF XY:

0.00186

AC XY:

138

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00670

AC:

278

AN:

41512

American (AMR)

AF:

0.000393

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.000416

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68000

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.000714

Hom.:

Bravo

AF:

0.00213

ESP6500AA

AF:

0.00499

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000675

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Muscle AMP deaminase deficiency (3)

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.077

MetaSVM

Uncertain

0.77

MutationAssessor

Pathogenic

3.6

PhyloP100

2.9

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.8

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.99

MVP

0.98

MPC

0.46

ClinPred

0.12

GERP RS

1.9

Varity_R

0.86

gMVP

0.95

Mutation Taster

=44/56

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over