1-114684369-CAAAA-CAAAAAAA

Variant names:

• chr1-114684369-C-CAAA
• rs727503806
• NM_000036.3:c.382-8_382-6dupTTT

Variant summary

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

The NM_000036.3(AMPD1):​c.382-8_382-6dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000887 in 1,126,822 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.9e-7 (0 hom.)
• Consequence: AMPD1 NM_000036.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05
• Publications: 0 publications found

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

ACMG classification

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	c.382-8_382-6dupTTT		splice_region_variant, intron_variant	Intron 4 of 15	ENST00000520113.7	NP_000027.3
AMPD1	NM_001172626.2	c.370-8_370-6dupTTT		splice_region_variant, intron_variant	Intron 3 of 14		NP_001166097.2

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.87e-7 AC: 1 AN: 1126822 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 564008

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

African (AFR) AF: 0.00 AC: 0 AN: 25838

American (AMR) AF: 0.00 AC: 0 AN: 36198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20808

East Asian (EAS) AF: 0.00 AC: 0 AN: 31134

South Asian (SAS) AF: 0.00 AC: 0 AN: 71794

European-Finnish (FIN) AF: 0.0000244 AC: 1 AN: 40980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4770

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 848514

Other (OTH) AF: 0.00 AC: 0 AN: 46786

⚠️ 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.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727503806; hg19: chr1-115226990;