rs35859650

Positions:

• chr1-114677972-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP3 BP4_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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3 B:1
• Conservation: PhyloP100: 2.85

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, M_CAP, MutationAssessor, PrimateAI, PROVEAN, 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/exons	MANE	Protein	UniProt
AMPD1	NM_000036.3	c.1162C>T	p.Arg388Trp	missense_variant	9/16	ENST00000520113.7	NP_000027.3
AMPD1	NM_001172626.2	c.1150C>T	p.Arg384Trp	missense_variant	8/15		NP_001166097.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMPD1	ENST00000520113.7	c.1162C>T	p.Arg388Trp	missense_variant	9/16	1	NM_000036.3	ENSP00000430075.3

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 292 AN: 151998 Hom.: 1 Cov.: 31

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

GnomAD3 exomes AF: 0.000565 AC: 142 AN: 251462 Hom.: 1 AF XY: 0.000397 AC XY: 54 AN XY: 135906

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 SAS exome AF: 0.00

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.: 1 Cov.: 33 AF XY: 0.000169 AC XY: 123 AN XY: 727192

Gnomad4 AFR exome AF: 0.00627

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.00193 AC: 293 AN: 152116 Hom.: 1 Cov.: 31 AF XY: 0.00186 AC XY: 138 AN XY: 74350

Gnomad4 AFR AF: 0.00670

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000391 Hom.: 0

Bravo AF: 0.00213

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000675 AC: 82

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Muscle AMP deaminase deficiency Pathogenic:2 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2000	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

not provided Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 29, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2024	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) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 27, 2022

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	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.077	T;T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.6	H;.
PrimateAI	Pathogenic	0.89	D
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	T
GERP RS		1.9
Varity_R		0.86
gMVP		0.95

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: rs35859650; hg19: chr1-115220593; COSMIC: COSV100814994; COSMIC: COSV100814994;