rs35859650

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP3BP4_Moderate

The NM_000036.3(AMPD1):c.1162C>T(p.Arg388Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000369 in 1,613,898 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. R388Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

AMPD1
NM_000036.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.85

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, Dann, M_CAP, MutationAssessor, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.07670745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMPD1	NM_000036.3 link	c.1162C>T	p.Arg388Trp	missense_variant	Exon 9 of 16	ENST00000520113.7	NP_000027.3	P23109-1
AMPD1	NM_001172626.2 link	c.1150C>T	p.Arg384Trp	missense_variant	Exon 8 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.1162C>T	p.Arg388Trp	missense_variant	Exon 9 of 16	1	NM_000036.3	ENSP00000430075.3		P23109-1

Frequencies

GnomAD3 genomes

AF:

0.00192

AC:

292

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00669

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000394

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000565

AC:

142

AN:

251462

AF XY:

0.000397

show subpopulations

Gnomad AFR exome

AF:

0.00726

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000207

AC:

303

AN:

1461782

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

123

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00627

AC:

210

AN:

33480

Gnomad4 AMR exome

AF:

0.000358

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.0000383

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.000202

AC:

AN:

39698

Gnomad4 SAS exome

AF:

0.000116

AC:

AN:

86258

Gnomad4 FIN exome

AF:

0.0000749

AC:

AN:

53392

Gnomad4 NFE exome

AF:

0.0000189

AC:

AN:

1111930

Gnomad4 Remaining exome

AF:

0.000497

AC:

AN:

60396

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.00193

AC:

293

AN:

152116

Hom.:

Cov.:

AF XY:

0.00186

AC XY:

138

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00670

AC:

0.00669686

AN:

0.00669686

Gnomad4 AMR

AF:

0.000393

AC:

0.000393391

AN:

0.000393391

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000193

AC:

0.000193199

AN:

0.000193199

Gnomad4 SAS

AF:

0.000416

AC:

0.0004158

AN:

0.0004158

Gnomad4 FIN

AF:

0.000189

AC:

0.000189072

AN:

0.000189072

Gnomad4 NFE

AF:

0.0000441

AC:

0.0000441176

AN:

0.0000441176

Gnomad4 OTH

AF:

0.000474

AC:

0.000473934

AN:

0.000473934

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.000714

Hom.:

Bravo

AF:

0.00213

ESP6500AA

AF:

0.00499

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000675

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Muscle AMP deaminase deficiency

Pathogenic:2Benign:1

Oct 01, 2019

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1Uncertain:2

Sep 29, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 25, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect; specifically, expression studies of this variant form of AMPD1 in prokaryotic cells demonstrated undetectable enzyme activity despite normal quantities of AMPD1 peptides, as compared with controls (PMID: 11102975); This variant is associated with the following publications: (PMID: 34426522, Mohamed[article]2023, 10996775, 36846110, 11102975) -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The AMPD1 p.Arg417Trp variant was identified in dbSNP (ID: rs35859650) and ClinVar (classified as likely pathogenic by GeneDx and as a VUS by EGL Genetic Diagnostics) but was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 204 of 282854 chromosomes (2 homozygous) at a frequency of 0.000721 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: African in 178 of 24962 chromosomes (freq: 0.007131), Other in 5 of 7226 chromosomes (freq: 0.000692), Latino in 9 of 35440 chromosomes (freq: 0.000254), East Asian in 5 of 19952 chromosomes (freq: 0.000251), European (Finnish) in 3 of 25096 chromosomes (freq: 0.00012) and European (non-Finnish) in 4 of 129192 chromosomes (freq: 0.000031), while the variant was not observed in the Ashkenazi Jewish or South Asian populations. The R417W variant was found in the compound heterozygous state in a Japanese patient with myopathy; expression of the R417W vector compared to wildtype showed no AMPD protein activity from the R417W vector (Morisaki_2000_PMID:11102975). The p.Arg417 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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

Uncertain:1

Sep 27, 2022

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: AMPD1 c.1261C>T (p.Arg421Trp, also known as c.1162C>T, p.Arg388Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00056 in 251462 control chromosomes in the gnomAD database, including 1 homozygote. c.1261C>T has been reported as a biallelic genotype in the literature in at least one individual affected with Muscle AMP Deaminase Deficiency (Abe_2000, Morisaki_2000). These data do not allow any conclusion about variant significance. When expressed as a rat/human chimeric protein in a prokaryotic expression assay, the variant was found to potentially induce loss of function. However, it is not clear if this effect can be replicated in human cells with human mutant protein (Morisaki_2000). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, two as likely pathogenic, and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

D;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.077

T;T

MetaSVM

Uncertain

0.77

MutationAssessor

Pathogenic

3.6

H;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.8

D;D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.99

MVP

0.98

MPC

0.46

ClinPred

0.12

GERP RS

1.9

Varity_R

0.86

gMVP

0.95

Mutation Taster

=44/56

disease causing (ClinVar)

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