chr1-114678495-C-A

Position:

chr1-114678495-C-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BP4_StrongBS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 7.91

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 made for transcript

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 linkuse as main transcript	c.930G>T	p.Met310Ile	missense_variant	8/16	ENST00000520113.7	NP_000027.3
AMPD1	NM_001172626.2 linkuse as main transcript	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 linkuse as main transcript	c.930G>T	p.Met310Ile	missense_variant	8/16	1	NM_000036.3	ENSP00000430075	P4	P23109-1
AMPD1	ENST00000369538.4 linkuse as main transcript	c.918G>T	p.Met306Ile	missense_variant	7/15	2		ENSP00000358551	A1	P23109-2
AMPD1	ENST00000639077.1 linkuse as main transcript	n.595G>T		non_coding_transcript_exon_variant	5/13	5
AMPD1	ENST00000637080.1 linkuse as main transcript	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.:

Cov.:

show subpopulations

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.:

AF XY:

0.00329

AC XY:

447

AN XY:

135882

show subpopulations

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.:

Cov.:

AF XY:

0.00412

AC XY:

2999

AN XY:

727222

show subpopulations

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.:

Cov.:

AF XY:

0.00383

AC XY:

285

AN XY:

74472

show subpopulations

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.:

Bravo

AF:

0.00439

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00535

AC:

ExAC

AF:

0.00313

AC:

380

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00485

EpiControl

AF:

0.00575

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

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:3Benign: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

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

T;T

M_CAP

Pathogenic

0.55

MetaRNN

Benign

0.034

T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.82

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

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

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