rs139582106

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5BP4

The NM_000036.3(AMPD1):c.468G>T(p.Gln156His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000777 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q156K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00077 ( 0 hom. )

Consequence

AMPD1
NM_000036.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:2

Conservation

PhyloP100: 2.08

Publications

9 publications found

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 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

AMPD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP5

Variant 1-114684278-C-A is Pathogenic according to our data. Variant chr1-114684278-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197620.

BP4

Computational evidence support a benign effect (MetaRNN=0.2525351). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMPD1	NM_000036.3 link	c.468G>T	p.Gln156His	missense_variant	Exon 5 of 16	ENST00000520113.7	NP_000027.3	P23109-1
AMPD1	NM_001172626.2 link	c.456G>T	p.Gln152His	missense_variant	Exon 4 of 15		NP_001166097.2	P23109-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMPD1	ENST00000520113.7 link	c.468G>T	p.Gln156His	missense_variant	Exon 5 of 16	1	NM_000036.3	ENSP00000430075.3		P23109-1

Frequencies

GnomAD3 genomes

AF:

0.000888

AC:

135

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000537

AC:

135

AN:

251484

AF XY:

0.000559

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000914

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000765

AC:

1119

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000756

AC XY:

550

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000559

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000936

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000941

AC:

1046

AN:

1112012

Other (OTH)

AF:

0.000646

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

139

208

278

347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000888

AC:

135

AN:

152066

Hom.:

Cov.:

AF XY:

0.000956

AC XY:

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41398

American (AMR)

AF:

0.00373

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00103

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00101

Hom.:

Bravo

AF:

0.000827

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000445

AC:

EpiCase

AF:

0.00136

EpiControl

AF:

0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Muscle AMP deaminase deficiency

Pathogenic:4Uncertain:1

Jan 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 189 of the AMPD1 protein (p.Gln189His). This variant is present in population databases (rs139582106, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with myoadenylate deaminase deficiency (PMID: 12117480, 19353846, 29095874). This variant is also known as G468T (Q156H). ClinVar contains an entry for this variant (Variation ID: 197620). 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. Experimental studies have shown that this missense change affects AMPD1 function (PMID: 12117480). 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. -

Mar 24, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4_MOD,PM2. -

Nov 27, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: AMPD1 c.468G>T (p.Gln156His) results in a non-conservative amino acid change located in the AMP deaminase domain (IPR006329) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00054 in 251484 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in AMPD1 causing Muscle AMP Deaminase Deficiency, allowing no conclusion about variant significance. c.468G>T has been reported in the literature in multiple individuals affected with Muscle AMP Deaminase Deficiency (example, Gross_2002). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzymatic activity in vitro (Gross_2002). The following publication has been ascertained in the context of this evaluation (PMID: 12117480). ClinVar contains an entry for this variant (Variation ID: 197620). Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 31, 2023

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:4Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The AMPD1 p.Q189H variant was identified in the literature as a compound heterozygous variant in 10 individuals with myoadenylate deaminase deficiency (Gross_2002_PMID_12117480). The variant was identified in dbSNP (ID: rs139582106) and ClinVar (classified as likely pathogenic by EGL Genetic Diagnostics, Fulgent Genetics and GeneDx; classified as uncertain significance by Invitae). The variant was identified in control databases in 147 of 282856 chromosomes at a frequency of 0.0005197 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 115 of 129180 chromosomes (freq: 0.00089), Latino in 25 of 35440 chromosomes (freq: 0.000705), Other in 3 of 7226 chromosomes (freq: 0.000415), African in 2 of 24958 chromosomes (freq: 0.00008) and European (Finnish) in 2 of 25120 chromosomes (freq: 0.00008), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Q189 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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. Functional studies have demonstrated altered enzymatic activity from the p.Q189H variant compared to wildtype (Gross_2002_PMID_12117480). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

Jan 19, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported previously (as Q156H due to alternate nomenclature) in multiple individuals with MADA deficiency and myopathy who were compound heterozygous for the Q189H variant and the most common AMPD1 variant, Q45X (Gross et al., 2002; Neroldova et al., 2016; Rannou et al., 2017); Published functional studies demonstrate altered enzyme activity (Gross et al., 2002); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27296017, 12117480, 29095874, 34426522, 31980526, 32483371, 34269512) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AMPD1: PM3:Very Strong, PM2, PS3:Supporting -

Apr 07, 2015

Eurofins Ntd Llc (ga)

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.40

T;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.

PhyloP100

2.1

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.16

Sift

Benign

0.28

T;T

Sift4G

Benign

0.30

T;T

Vest4

0.79

MVP

0.45

MPC

0.41

ClinPred

0.81

GERP RS

2.9

Varity_R

0.12

gMVP

0.94

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over