1-114673175-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000036.3(AMPD1):c.2183G>A(p.Arg728His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R728C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: AMPD1 NM_000036.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMPD1	NM_000036.3	c.2183G>A	p.Arg728His	missense_variant	16/16	ENST00000520113.7
AMPD1	NM_001172626.2	c.2171G>A	p.Arg724His	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMPD1	ENST00000520113.7	c.2183G>A	p.Arg728His	missense_variant	16/16	1	NM_000036.3	P4

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251436 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135906

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727220

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74438

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000541 Hom.: 0

Bravo AF: 0.000234

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Muscle AMP deaminase deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 25, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 761 of the AMPD1 protein (p.Arg761His). This variant is present in population databases (rs142643298, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with AMPD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2139645). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 17, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.7	H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.98
MVP		0.90
MPC		0.50
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.69
gMVP		0.93

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

LitVar

Other links and lift over

dbSNP: rs142643298; hg19: chr1-115215796; COSMIC: COSV62415304; COSMIC: COSV62415304;