rs34526199

chr1-114679616-T-Achr1-114679616-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3 BP4_Strong BS1_Supporting BS2

The NM_000036.3(AMPD1):c.860A>T(p.Lys287Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 1,612,856 control chromosomes in the GnomAD database, including 976 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.026 (91 hom., cov: 32)
  • Exomes 𝑓: 0.032 (885 hom.)
• Consequence: AMPD1 NM_000036.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4 B:4 O:1
• Conservation: PhyloP100: 8.02

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 Benign. Variant got -8 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.005099088).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0265 (3999/151108) while in subpopulation NFE AF= 0.0344 (2325/67666). AF 95% confidence interval is 0.0332. There are 91 homozygotes in gnomad4. There are 2075 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 91 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMPD1	NM_000036.3	c.860A>T	p.Lys287Ile	missense_variant	7/16	ENST00000520113.7
AMPD1	NM_001172626.2	c.848A>T	p.Lys283Ile	missense_variant	6/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMPD1	ENST00000520113.7	c.860A>T	p.Lys287Ile	missense_variant	7/16	1	NM_000036.3	P4
AMPD1	ENST00000369538.4	c.848A>T	p.Lys283Ile	missense_variant	6/15	2		A1
AMPD1	ENST00000639077.1	n.525A>T		non_coding_transcript_exon_variant	4/13	5
AMPD1	ENST00000637080.1	c.*67A>T		3_prime_UTR_variant, NMD_transcript_variant	5/14	5

Frequencies

GnomAD3 genomes AF: 0.0265 AC: 4000 AN: 150990 Hom.: 91 Cov.: 32

Gnomad AFR AF: 0.00542

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.0235

Gnomad EAS AF: 0.000585

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0847

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.0226

GnomAD3 exomes AF: 0.0283 AC: 7112 AN: 251474 Hom.: 153 AF XY: 0.0287 AC XY: 3907 AN XY: 135912

Gnomad AFR exome AF: 0.00437

Gnomad AMR exome AF: 0.0155

Gnomad ASJ exome AF: 0.0241

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0155

Gnomad FIN exome AF: 0.0830

Gnomad NFE exome AF: 0.0335

Gnomad OTH exome AF: 0.0296

GnomAD4 exome AF: 0.0316 AC: 46263 AN: 1461748 Hom.: 885 Cov.: 32 AF XY: 0.0314 AC XY: 22810 AN XY: 727184

Gnomad4 AFR exome AF: 0.00439

Gnomad4 AMR exome AF: 0.0159

Gnomad4 ASJ exome AF: 0.0238

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0155

Gnomad4 FIN exome AF: 0.0803

Gnomad4 NFE exome AF: 0.0335

Gnomad4 OTH exome AF: 0.0299

GnomAD4 genome AF: 0.0265 AC: 3999 AN: 151108 Hom.: 91 Cov.: 32 AF XY: 0.0281 AC XY: 2075 AN XY: 73888

Gnomad4 AFR AF: 0.00541

Gnomad4 AMR AF: 0.0164

Gnomad4 ASJ AF: 0.0235

Gnomad4 EAS AF: 0.000586

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.0847

Gnomad4 NFE AF: 0.0344

Gnomad4 OTH AF: 0.0224

Alfa AF: 0.0304 Hom.: 69

Bravo AF: 0.0207

TwinsUK AF: 0.0372 AC: 138

ALSPAC AF: 0.0353 AC: 136

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0344 AC: 296

ExAC AF: 0.0282 AC: 3425

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0317

EpiControl AF: 0.0287

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Muscle AMP deaminase deficiency Pathogenic:2 Uncertain:1 Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM3,PP3,PP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 26, 2020	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Uncertain significance and reported on 05-17-2017 by Lab or GTR ID 303161. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Pathogenic:1 Uncertain:2

Likely pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	 The AMPD1 p.Lys320Ile variant was identified in the literature as a heterozygous variant in a patient with muscular dystrophy, however this patient also harbored biallelic loss of function variants in the LAMA2 gene that were attributed as the cause of disease (Russo_2014_PMID:25332755). The variant was also identified in dbSNP (ID: rs34526199) and ClinVar (conflicting interpretations of pathogenicity with two likely pathogenic submissions by Fulgent Genetics and Mayo Clinic Genetic Testing Laboratories and one VUS submission by EGL Genetics Diagnostics; associated condition is Muscle AMP deaminase deficiency). The variant was identified in control databases in 8126 of 282682 chromosomes (174 homozygous) at a frequency of 0.028746 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations:  European (Finnish) in 2089 of 25116 chromosomes (freq: 0.08317), European (non-Finnish) in 4407 of 129122 chromosomes (freq: 0.03413), Other in 234 of 7220 chromosomes (freq: 0.03241), Ashkenazi Jewish in 252 of 10368 chromosomes (freq: 0.02431), Latino in 553 of 35440 chromosomes (freq: 0.0156), South Asian in 473 of 30614 chromosomes (freq: 0.01545) and African in 118 of 24852 chromosomes (freq: 0.004748), while the variant was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Lys320 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the K variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 01, 2024	The p.Lys287Ile variant in AMPD1 is classified as likely benign because it has been identified in 13.0% (118/910) of Amish and 8.4% (894/10552) of European chromosomes including 91 homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). ACMG/AMP Criteria applied: BS1. -

Hypercholesterolemia, autosomal dominant, type B;C3714933:Muscle AMP deaminase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Dec 07, 2022

- -

AMPD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2021

This variant is classified as 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
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0051	T;T
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.8	H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.9	D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.35
MPC		0.60
ClinPred		0.87	D
GERP RS		5.6
Varity_R		0.88
gMVP		0.75

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: rs34526199; hg19: chr1-115222237; COSMIC: COSV62419428; COSMIC: COSV62419428;