Genetic Variant AMPD1:c.382-7_382-6delTT (chr1-114684369-CAA-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000036.3(AMPD1):c.382-7_382-6delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,124,668 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AMPD1
NM_000036.3 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.99

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMPD1	NM_000036.3 link	c.382-7_382-6delTT		splice_region_variant, intron_variant	Intron 4 of 15	ENST00000520113.7	NP_000027.3	P23109-1
AMPD1	NM_001172626.2 link	c.370-7_370-6delTT		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.382-7_382-6delTT		splice_region_variant, intron_variant	Intron 4 of 15	1	NM_000036.3	ENSP00000430075.3		P23109-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

134456

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000255

AC:

AN:

70624

AF XY:

0.000188

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000429

Gnomad FIN exome

AF:

0.000878

Gnomad NFE exome

AF:

0.000297

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1124668

Hom.:

AF XY:

0.0000142

AC XY:

AN XY:

562978

show subpopulations

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

African (AFR)

AF:

0.0000388

AC:

AN:

25782

American (AMR)

AF:

0.00

AC:

AN:

36144

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20774

East Asian (EAS)

AF:

0.00

AC:

AN:

31064

South Asian (SAS)

AF:

0.00

AC:

AN:

71712

European-Finnish (FIN)

AF:

0.000171

AC:

AN:

40820

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4762

European-Non Finnish (NFE)

AF:

0.00000472

AC:

AN:

846930

Other (OTH)

AF:

0.0000214

AC:

AN:

46680

⚠️ 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: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

134456

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

64854

African (AFR)

AF:

0.00

AC:

AN:

36552

American (AMR)

AF:

0.00

AC:

AN:

13272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3220

East Asian (EAS)

AF:

0.00

AC:

AN:

4738

South Asian (SAS)

AF:

0.00

AC:

AN:

4210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7764

Middle Eastern (MID)

AF:

0.00

AC:

AN:

296

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

61778

Other (OTH)

AF:

0.00

AC:

AN:

1808

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.0

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over