rs17602729

Positions:

• chr1-114693436-G-A
• chr1-114693436-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PVS1_Strong BA1

The NM_000036.3(AMPD1):​c.34C>T​(p.Gln12Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,600,304 control chromosomes in the GnomAD database, including 10,624 homozygotes. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars).

• Frequency:
  • Genomes: 𝑓 0.085 (761 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9863 hom.)
• Consequence: AMPD1 NM_000036.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.04374
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:2 U:6 B:3 O:2
• Conservation: PhyloP100: 3.47

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 Likely_benign. Variant got -4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMPD1	NM_000036.3	c.34C>T	p.Gln12Ter	stop_gained, splice_region_variant	2/16	ENST00000520113.7
AMPD1	NM_001172626.2	c.22+2014C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMPD1	ENST00000520113.7	c.34C>T	p.Gln12Ter	stop_gained, splice_region_variant	2/16	1	NM_000036.3	P4
AMPD1	ENST00000369538.4	c.22+2014C>T		intron_variant		2		A1
AMPD1	ENST00000637080.1	c.37+2001C>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0850 AC: 12903 AN: 151842 Hom.: 761 Cov.: 32

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.0704

Gnomad ASJ AF: 0.0721

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0282

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0924

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.0817

GnomAD3 exomes AF: 0.0860 AC: 21605 AN: 251114 Hom.: 1271 AF XY: 0.0872 AC XY: 11833 AN XY: 135768

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.0492

Gnomad ASJ exome AF: 0.0758

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0352

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.0921

GnomAD4 exome AF: 0.109 AC: 157715 AN: 1448344 Hom.: 9863 Cov.: 29 AF XY: 0.107 AC XY: 77257 AN XY: 721124

Gnomad4 AFR exome AF: 0.0164

Gnomad4 AMR exome AF: 0.0506

Gnomad4 ASJ exome AF: 0.0773

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.0347

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.125

Gnomad4 OTH exome AF: 0.0984

GnomAD4 genome AF: 0.0849 AC: 12901 AN: 151960 Hom.: 761 Cov.: 32 AF XY: 0.0821 AC XY: 6094 AN XY: 74240

Gnomad4 AFR AF: 0.0217

Gnomad4 AMR AF: 0.0703

Gnomad4 ASJ AF: 0.0721

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.0278

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.0803

Alfa AF: 0.117 Hom.: 2226

Bravo AF: 0.0779

TwinsUK AF: 0.139 AC: 515

ALSPAC AF: 0.123 AC: 475

ESP6500AA AF: 0.0236 AC: 104

ESP6500EA AF: 0.131 AC: 1126

ExAC AF: 0.0870 AC: 10566

Asia WGS AF: 0.0220 AC: 77 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity; other

Submissions summary: Pathogenic:2 Uncertain:6 Benign:3 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Muscle AMP deaminase deficiency Pathogenic:1 Uncertain:3 Benign:1 Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	Jan 06, 2021	The p.Gln45* variant in the AMPD1 gene has been previously reported in >20 unrelated individuals, some were asymptomatic and others had features consistent with myoadenylate deaminase deficiency. All individuals were homozygous/compound heterozygous although some had variants in other genes that may be alternate explanations for those individuals’ features (Castro-Gago et al., 2011; Morisaki et al., 1992; Pantoja-Martinez et la., 2004; Rannou et al, 2017; Rubio et al., 2000). The highest allele frequency of the p.Gln45* variant was identified in the European population at 16,882/128,928 chromosomes (13.09%) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant leads to a premature stop codon in exon 2 of 16 coding exons and is therefore predicted to undergo nonsense-mediated decay resulting in a truncated or absent protein. Loss of AMPD1 function is a possible mechanism of disease, and data from functional studies suggests this gene is intolerant to variants that result in loss of function (Castro-Gago et al., 2011; Morisaki et al., 1992). Functional studies of the p.Gln45* variant are supportive of a deleterious effect to the protein; however, it is unclear if this would be sufficient to be disease-causing (Castro-Gago et al., 2011; Morisaki et al., 1992). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Gln45* variant is uncertain due to conflicting allele frequency, clinical, and functional evidence. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PVS1_moderate; PS3_moderate] -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 30, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 21, 2019	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP4,BA1,BS2. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 02, 2022	This sequence change creates a premature translational stop signal (p.Gln45*) in the AMPD1 gene. However, alternative splicing may rescue certain truncations, particularly those occurring in exon 2 (PMID: 1922051). It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in AMPD1 cause disease. This variant is present in population databases (rs17602729, gnomAD 13%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with adenosine monophosphate deaminase deficiency (PMID: 1631143, 8335021, 15378456, 21343608). It has also been observed to segregate with disease in related individuals. This variant is also known as c.34C>T (p.Gln12*). ClinVar contains an entry for this variant (Variation ID: 18271). 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. -

not provided Pathogenic:1 Uncertain:2 Benign:1 Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The AMPD1 p.Gln45* variant has been reported in multiple homozygous individuals with AMPD deficiency but has also been reported in multiple healthy controls, including athletes (Morisaki_1992_PMID:1631143; Gronek_2018_PMID:30429902; Nikolova_2015_PMID:26380113; Gineviciene_2014_PMID:24885427). The variant was identified in dbSNP (ID: rs17602729) and ClinVar (classified as uncertain significance by GeneDx and Invitae, and as pathogenic by Mayo Clinic). The variant was identified in control databases in 24609 of 282334 chromosomes (1470 homozygous) at a frequency of 0.08716 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 16882 of 128928 chromosomes (freq: 0.1309), European (Finnish) in 2903 of 25048 chromosomes (freq: 0.1159), Other in 682 of 7188 chromosomes (freq: 0.09488), Ashkenazi Jewish in 790 of 10360 chromosomes (freq: 0.07625), Latino in 1757 of 35356 chromosomes (freq: 0.04969), South Asian in 1078 of 30602 chromosomes (freq: 0.03523), African in 516 of 24900 chromosomes (freq: 0.02072), and East Asian in 1 of 19952 chromosomes (freq: 0.00005). The c.133C>T variant leads to a premature stop codon at position 45, which is predicted to lead to a truncated or absent protein and loss of function. It is unclear how loss of function variants of the AMPD1 gene contribute to autosomal recessive AMPD deficiency; further, many individuals with AMPD deficiency are asymptomatic. The p.Gln45* variant occurs in the last base of the exon; this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	AMPD1: BS1, BS2 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21686757, 29143670, 29095874, 25525159, 8335021, 32596782, 32483371, 33250842, 15239633, 15378456, 14499869, 23300193, 16021918, 18855224, 1631143, 12117480, 21343608, 10918252, 29422864, 29749052, 30429902, 28751290, 30837873, 31867206, 32379996, 24508110, 35309536, 33879512, 35821574, 36112609, 32639377) -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 07, 2018	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 13, 2023

Variant summary: AMPD1 c.34C>T (p.Gln12X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. Most truncations downstream of this position have been classified as uncertain significance in ClinVar. The variant allele was found at a frequency of 0.086 in 251114 control chromosomes, predominantly at a frequency of 0.13 within the Non-Finnish European subpopulation in the gnomAD database, including 986 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.16 fold of the estimated maximal expected allele frequency for a pathogenic variant in AMPD1 causing Muscle AMP Deaminase Deficiency phenotype (0.11), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.34C>T has been reported in the literature in multiple homozygous and heterozygous individuals affected with Muscle AMP Deaminase Deficiency (Morisaki_1992, Rannou_2017). These data indicate that the variant is very likely to be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and this variant results in decreasing normal AMPD activity (Morisaki_1992, Kalsi_2003, Rannou_2017). Seven ClinVar submitters (evaluation after 2014) cite this variant as pathogenic (n=3), uncertain significance (n=3) and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

AMPD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	2.4e-26	P;P;P
Vest4		0.78
GERP RS		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.044
dbscSNV1_RF	Benign	0.21
SpliceAI score (max)		0.040		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: rs17602729; hg19: chr1-115236057; COSMIC: COSV62415596; COSMIC: COSV62415596;