rs61752478

Positions:

• chr1-114678495-C-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3 BP4_Strong BS2

The NM_000036.3(AMPD1):​c.930G>T​(p.Met310Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00413 in 1,614,150 control chromosomes in the GnomAD database, including 18 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 0.0038 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0042 (16 hom.)
• Consequence: AMPD1 NM_000036.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 7.91

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 -7 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, phyloP100way_vertebrate, PrimateAI, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.033944935).
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMPD1	NM_000036.3	c.930G>T	p.Met310Ile	missense_variant	8/16	ENST00000520113.7	NP_000027.3
AMPD1	NM_001172626.2	c.918G>T	p.Met306Ile	missense_variant	7/15		NP_001166097.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMPD1	ENST00000520113.7	c.930G>T	p.Met310Ile	missense_variant	8/16	1	NM_000036.3	ENSP00000430075	P4
AMPD1	ENST00000369538.4	c.918G>T	p.Met306Ile	missense_variant	7/15	2		ENSP00000358551	A1
AMPD1	ENST00000639077.1	n.595G>T		non_coding_transcript_exon_variant	5/13	5
AMPD1	ENST00000637080.1	c.*137G>T		3_prime_UTR_variant, NMD_transcript_variant	6/14	5		ENSP00000489753

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 573 AN: 152184 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00459

Gnomad OTH AF: 0.00959

GnomAD3 exomes AF: 0.00330 AC: 829 AN: 251424 Hom.: 3 AF XY: 0.00329 AC XY: 447 AN XY: 135882

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00483

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00477

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00417 AC: 6100 AN: 1461848 Hom.: 16 Cov.: 32 AF XY: 0.00412 AC XY: 2999 AN XY: 727222

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00492

Gnomad4 ASJ exome AF: 0.00635

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.00484

Gnomad4 OTH exome AF: 0.00404

GnomAD4 genome AF: 0.00376 AC: 573 AN: 152302 Hom.: 2 Cov.: 31 AF XY: 0.00383 AC XY: 285 AN XY: 74472

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00459

Gnomad4 OTH AF: 0.00949

Alfa AF: 0.00420 Hom.: 1

Bravo AF: 0.00439

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00313 AC: 380

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00485

EpiControl AF: 0.00575

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2021	Identified in a patient with familial hypercholesterolemia (Johansen et al., 2014), although the association of this variant with this lipid disorder is unclear; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24503134, 26764160, 15173240, 29431110, 32054689, 31130284) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 24, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -

Muscle AMP deaminase deficiency Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 03, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 26, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	Jan 06, 2021	The p.Met343Ile variant in the AMPD1 gene has been previously reported in at least 3 unrelated individuals, including 1 individual who was heterozygous for this variant with progressive muscle weakness, high creatine, and utilized a wheelchair (Monies et al., 2019), 1 individual with myopathy without information to determine zygosity (Toyama et al., 2004), and at least 1 individual without information regarding clinical features or information to determine zygosity (Reuter et al., 2018). The highest allele frequency of this variant in a non-founder population was identified in the Latino/Admixed American population at 170/35,438 chromosomes (0.48%) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Functional studies of the p.Met343Ile variant are supportive of a deleterious effect to the protein; however, it is unclear if this would be sufficient to be disease-causing (Toyama et al., 2004). Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Met343Ile variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PP3] -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 19, 2023

Variant summary: AMPD1 c.930G>T (p.Met310Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0033 in 251424 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency does not allowing conclusions about variant significance, although the presence of homozygotes points to a benign outcome for a condition with full penetrance expected at an early age. Although c.930G>T has been reported in the literature, these report(s) do not provide unequivocal conclusions about association of the variant with Muscle AMP Deaminase Deficiency (example, PMID: 24503134, 31847883). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=6; LB, n=1). 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	0.99
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.034	T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.87
MVP		0.98
MPC		0.36
ClinPred		0.035	T
GERP RS		5.1
Varity_R		0.88
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs61752478; hg19: chr1-115221116; COSMIC: COSV99055584; COSMIC: COSV99055584;