1-114677465-C-T

Position:

chr1-114677465-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP3BP4_Strong

The ENST00000520113.7(AMPD1):c.1274G>A(p.Arg425His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,613,158 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R425C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

AMPD1
ENST00000520113.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3B: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 Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

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

BP4

Computational evidence support a benign effect (MetaRNN=0.018382728).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMPD1	NM_000036.3 linkuse as main transcript	c.1274G>A	p.Arg425His	missense_variant	10/16	ENST00000520113.7	NP_000027.3
AMPD1	NM_001172626.2 linkuse as main transcript	c.1262G>A	p.Arg421His	missense_variant	9/15		NP_001166097.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMPD1	ENST00000520113.7 linkuse as main transcript	c.1274G>A	p.Arg425His	missense_variant	10/16	1	NM_000036.3	ENSP00000430075	P4	P23109-1
AMPD1	ENST00000369538.4 linkuse as main transcript	c.1262G>A	p.Arg421His	missense_variant	9/15	2		ENSP00000358551	A1	P23109-2
AMPD1	ENST00000639077.1 linkuse as main transcript	n.939G>A		non_coding_transcript_exon_variant	7/13	5
AMPD1	ENST00000637080.1 linkuse as main transcript	c.*481G>A		3_prime_UTR_variant, NMD_transcript_variant	8/14	5		ENSP00000489753

Frequencies

GnomAD3 genomes

AF:

0.000410

AC:

AN:

151150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000528

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00933

Gnomad SAS

AF:

0.000421

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00145

GnomAD3 exomes

AF:

0.000875

AC:

220

AN:

251428

Hom.:

AF XY:

0.000839

AC XY:

114

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0114

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000242

AC:

354

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000252

AC XY:

183

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00733

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000546

GnomAD4 genome

AF:

0.000410

AC:

AN:

151266

Hom.:

Cov.:

AF XY:

0.000528

AC XY:

AN XY:

73846

show subpopulations

Gnomad4 AFR

AF:

0.0000243

Gnomad4 AMR

AF:

0.000528

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00935

Gnomad4 SAS

AF:

0.000422

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00144

Alfa

AF:

0.0000964

Hom.:

Bravo

AF:

0.000442

ExAC

AF:

0.000774

AC:

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Muscle AMP deaminase deficiency

Pathogenic:2Uncertain:1Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2000	- -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 14, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 10, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D

MetaRNN

Benign

0.018

T;T

MetaSVM

Uncertain

0.72

MutationAssessor

Pathogenic

3.3

M;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-4.9

D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.92

MVP

0.97

MPC

0.50

ClinPred

0.22

GERP RS

5.8

Varity_R

0.76

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

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