rs34526199

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP4_StrongBS1_SupportingBS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5B:4O:1

Conservation

PhyloP100: 8.02

Variant links:

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 links:

AMPD1 (HGNC:):

AMPD1 links:

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ACMG classification

Classification made for transcript

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. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 91 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMPD1	NM_000036.3 linkuse as main transcript	c.860A>T	p.Lys287Ile	missense_variant	7/16	ENST00000520113.7	NP_000027.3	P23109-1
AMPD1	NM_001172626.2 linkuse as main transcript	c.848A>T	p.Lys283Ile	missense_variant	6/15		NP_001166097.2	P23109-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMPD1	ENST00000520113.7 linkuse as main transcript	c.860A>T	p.Lys287Ile	missense_variant	7/16	1	NM_000036.3	ENSP00000430075.3		P23109-1

Frequencies

GnomAD3 genomes

AF:

0.0265

AC:

4000

AN:

150990

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0314

AC XY:

22810

AN XY:

727184

show subpopulations

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.:

Cov.:

AF XY:

0.0281

AC XY:

2075

AN XY:

73888

show subpopulations

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.:

Bravo

AF:

0.0207

TwinsUK

AF:

0.0372

AC:

138

ALSPAC

AF:

0.0353

AC:

136

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0344

AC:

296

ExAC

AF:

0.0282

AC:

3425

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0317

EpiControl

AF:

0.0287

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Muscle AMP deaminase deficiency

Pathogenic:2Uncertain:1Benign:1Other:1

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 26, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
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. -

not provided

Pathogenic:1Uncertain:3

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, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2024	Published functional studies found this variant is associated with reduced catalytic activity (PMID: 15173240); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(K287I); This variant is associated with the following publications: (PMID: 36199823, 32512653, 20981092, 24503134, 22995991, 29095874, 33250842, 33567613, 37789688, 15173240, 25332755) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Â¬â€ 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: Â¬â€ 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

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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

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, no assertion criteria provided

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

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.76

T;T

MetaRNN

Benign

0.0051

T;T

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

3.8

H;.

PrimateAI

Uncertain

0.77

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over