1-114684369-CAAAA-CAAAAA

Variant names:

• chr1-114684369-C-CA
• rs727503806
• NM_000036.3:c.382-6dupT

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 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 VariationId is 291934.

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.382-6dupT		splice_region intron	N/A	NP_000027.3	P23109-1
	AMPD1	NM_001172626.2		c.370-6dupT		splice_region intron	N/A	NP_001166097.2	P23109-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMPD1	ENST00000520113.7	TSL:1 MANE Select	c.382-6_382-5insT		splice_region intron	N/A	ENSP00000430075.3	P23109-1
	AMPD1	ENST00000369538.4	TSL:2	c.370-6_370-5insT		splice_region intron	N/A	ENSP00000358551.4	P23109-2
	AMPD1	ENST00000485564.3	TSL:5	n.256-6_256-5insT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 153 AN: 134380 Hom.: 0 Cov.: 32

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

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.: 0 Cov.: 0 AF XY: 0.0444 AC XY: 18359 AN XY: 413154

⚠️ 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), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00113 AC: 152 AN: 134414 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 83 AN XY: 64854

African (AFR) AF: 0.00281 AC: 103 AN: 36622

American (AMR) AF: 0.000527 AC: 7 AN: 13284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3218

East Asian (EAS) AF: 0.000424 AC: 2 AN: 4720

South Asian (SAS) AF: 0.00143 AC: 6 AN: 4192

European-Finnish (FIN) AF: 0.00219 AC: 17 AN: 7752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.000275 AC: 17 AN: 61716

Other (OTH) AF: 0.00 AC: 0 AN: 1818

Alfa AF: 0.0543 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Muscle AMP deaminase deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=97/3	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs727503806;

hg19: chr1-115226990;

COSMIC: COSV62417265;