chr1-114693436-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PVS1_StrongBA1

The NM_000036.3(AMPD1):c.34C>T(p.Gln12*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,600,304 control chromosomes in the GnomAD database, including 10,624 homozygotes. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars).

Frequency

Genomes: 𝑓 0.085 ( 761 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9863 hom. )

Consequence

AMPD1
NM_000036.3 stop_gained, splice_region

Scores

Splicing: ADA: 0.04374

Clinical Significance

Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:2U:7B:4O:2

Conservation

PhyloP100: 3.47

Publications

188 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: Likely_benign. The variant received -4 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.985 CDS is truncated, and there are 3 pathogenic variants in the truncated region.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

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.34C>T	p.Gln12*	stop_gained splice_region	Exon 2 of 16	NP_000027.3	P23109-1
	AMPD1	NM_001172626.2		c.22+2014C>T		intron	N/A	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.34C>T	p.Gln12*	stop_gained splice_region	Exon 2 of 16	ENSP00000430075.3	P23109-1
AMPD1	ENST00000369538.4	TSL:2	c.22+2014C>T		intron	N/A	ENSP00000358551.4	P23109-2
AMPD1	ENST00000637080.1	TSL:5	n.37+2001C>T		intron	N/A	ENSP00000489753.1	A0A1B0GTL6

Frequencies

GnomAD3 genomes

AF:

0.0850

AC:

12903

AN:

151842

Hom.:

761

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0218

Gnomad AMI

AF:

0.124

Gnomad AMR

AF:

0.0704

Gnomad ASJ

AF:

0.0721

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.0282

Gnomad FIN

AF:

0.118

Gnomad MID

AF:

0.0924

Gnomad NFE

AF:

0.132

Gnomad OTH

AF:

0.0817

GnomAD2 exomes

AF:

0.0860

AC:

21605

AN:

251114

AF XY:

0.0872

show subpopulations

Gnomad AFR exome

AF:

0.0201

Gnomad AMR exome

AF:

0.0492

Gnomad ASJ exome

AF:

0.0758

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.116

Gnomad NFE exome

AF:

0.129

Gnomad OTH exome

AF:

0.0921

GnomAD4 exome

AF:

0.109

AC:

157715

AN:

1448344

Hom.:

9863

Cov.:

AF XY:

0.107

AC XY:

77257

AN XY:

721124

show subpopulations

African (AFR)

AF:

0.0164

AC:

549

AN:

33388

American (AMR)

AF:

0.0506

AC:

2260

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.0773

AC:

2012

AN:

26020

East Asian (EAS)

AF:

0.000152

AC:

AN:

39570

South Asian (SAS)

AF:

0.0347

AC:

2985

AN:

86056

European-Finnish (FIN)

AF:

0.116

AC:

6184

AN:

53118

Middle Eastern (MID)

AF:

0.0657

AC:

377

AN:

5738

European-Non Finnish (NFE)

AF:

0.125

AC:

137449

AN:

1099910

Other (OTH)

AF:

0.0984

AC:

5893

AN:

59896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.424

Heterozygous variant carriers

6000

12000

18001

24001

30001

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4666

9332

13998

18664

23330

<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:

0.0849

AC:

12901

AN:

151960

Hom.:

761

Cov.:

AF XY:

0.0821

AC XY:

6094

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.0217

AC:

902

AN:

41490

American (AMR)

AF:

0.0703

AC:

1072

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.0721

AC:

250

AN:

3468

East Asian (EAS)

AF:

0.000581

AC:

AN:

5160

South Asian (SAS)

AF:

0.0278

AC:

134

AN:

4816

European-Finnish (FIN)

AF:

0.118

AC:

1239

AN:

10500

Middle Eastern (MID)

AF:

0.0959

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.132

AC:

8991

AN:

67962

Other (OTH)

AF:

0.0803

AC:

169

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

576

1151

1727

2302

2878

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

296

444

592

740

<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.:

4295

Bravo

AF:

0.0779

TwinsUK

AF:

0.139

AC:

515

ALSPAC

AF:

0.123

AC:

475

ESP6500AA

AF:

0.0236

AC:

104

ESP6500EA

AF:

0.131

AC:

1126

ExAC

AF:

0.0870

AC:

10566

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity; other

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Muscle AMP deaminase deficiency (7)

not provided (5)

not specified (2)

AMPD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.85

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.89

PhyloP100

3.5

Vest4

0.78

GERP RS

2.8

Mutation Taster

=170/30

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.044

dbscSNV1_RF

Benign

0.21

Splicevardb

2.0

SpliceAI score (max)

0.040

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