NM_000036.3:c.382-6dupT

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP6

The NM_000036.3(AMPD1):c.382-6dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0398 in 961,800 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.046 ( 0 hom. )

Consequence

AMPD1
NM_000036.3 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.05

Publications

0 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 1 ACMG points.

PM2

Variant has high frequency in the AFR (0.0494) population. However there is too low homozygotes in high coverage region: (expected more than 381, got 0).

BP6

Variant 1-114684369-C-CA is Benign according to our data. Variant chr1-114684369-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 291934.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMPD1	NM_000036.3 link	c.382-6dupT		splice_region_variant, intron_variant	Intron 4 of 15	ENST00000520113.7	NP_000027.3	P23109-1
AMPD1	NM_001172626.2 link	c.370-6dupT		splice_region_variant, intron_variant	Intron 3 of 14		NP_001166097.2	P23109-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMPD1	ENST00000520113.7 link	c.382-6_382-5insT		splice_region_variant, intron_variant	Intron 4 of 15	1	NM_000036.3	ENSP00000430075.3		P23109-1

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

153

AN:

134380

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00282

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000528

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000422

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00219

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000275

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0838

AC:

5918

AN:

70624

AF XY:

0.0853

show subpopulations

Gnomad AFR exome

AF:

0.0801

Gnomad AMR exome

AF:

0.100

Gnomad ASJ exome

AF:

0.0705

Gnomad EAS exome

AF:

0.0877

Gnomad FIN exome

AF:

0.0821

Gnomad NFE exome

AF:

0.0719

Gnomad OTH exome

AF:

0.0968

GnomAD4 exome

AF:

0.0461

AC:

38149

AN:

827386

Hom.:

Cov.:

AF XY:

0.0444

AC XY:

18359

AN XY:

413154

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0521

AC:

986

AN:

18918

American (AMR)

AF:

0.0466

AC:

1262

AN:

27064

Ashkenazi Jewish (ASJ)

AF:

0.0442

AC:

669

AN:

15148

East Asian (EAS)

AF:

0.0461

AC:

1046

AN:

22678

South Asian (SAS)

AF:

0.0361

AC:

1856

AN:

51378

European-Finnish (FIN)

AF:

0.0467

AC:

1533

AN:

32856

Middle Eastern (MID)

AF:

0.0360

AC:

143

AN:

3970

European-Non Finnish (NFE)

AF:

0.0467

AC:

28979

AN:

620930

Other (OTH)

AF:

0.0486

AC:

1675

AN:

34444

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.240

Heterozygous variant carriers

6440

12880

19321

25761

32201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

1120

2240

3360

4480

5600

<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:

0.00113

AC:

152

AN:

134414

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

64854

show subpopulations

African (AFR)

AF:

0.00281

AC:

103

AN:

36622

American (AMR)

AF:

0.000527

AC:

AN:

13284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3218

East Asian (EAS)

AF:

0.000424

AC:

AN:

4720

South Asian (SAS)

AF:

0.00143

AC:

AN:

4192

European-Finnish (FIN)

AF:

0.00219

AC:

AN:

7752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.000275

AC:

AN:

61716

Other (OTH)

AF:

0.00

AC:

AN:

1818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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:

0.0543

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Muscle AMP deaminase deficiency

Uncertain:1Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 12, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.0

Mutation Taster

=97/3

polymorphism

(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