1-114688633-G-A

Position:

• chr1-114688633-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000520113.7(AMPD1):​c.143C>T​(p.Pro48Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,613,946 control chromosomes in the GnomAD database, including 11,561 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars). Synonymous variant affecting the same amino acid position (i.e. P48P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.086 (781 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10780 hom.)
• Consequence: AMPD1 ENST00000520113.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications U:2 B:5 O:1
• Conservation: PhyloP100: 9.35

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030060112).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMPD1	NM_000036.3	c.143C>T	p.Pro48Leu	missense_variant	3/16	ENST00000520113.7	NP_000027.3
AMPD1	NM_001172626.2	c.131C>T	p.Pro44Leu	missense_variant	2/15		NP_001166097.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMPD1	ENST00000520113.7	c.143C>T	p.Pro48Leu	missense_variant	3/16	1	NM_000036.3	ENSP00000430075	P4
AMPD1	ENST00000369538.4	c.131C>T	p.Pro44Leu	missense_variant	2/15	2		ENSP00000358551	A1
AMPD1	ENST00000637080.1	c.146C>T	p.Pro49Leu	missense_variant, NMD_transcript_variant	2/14	5		ENSP00000489753

Frequencies

GnomAD3 genomes AF: 0.0865 AC: 13148 AN: 152026 Hom.: 781 Cov.: 32

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.0727

Gnomad ASJ AF: 0.0735

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0282

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.0839

GnomAD3 exomes AF: 0.0876 AC: 22018 AN: 251420 Hom.: 1331 AF XY: 0.0888 AC XY: 12065 AN XY: 135876

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.0509

Gnomad ASJ exome AF: 0.0768

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0355

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.132

Gnomad OTH exome AF: 0.0932

GnomAD4 exome AF: 0.115 AC: 167963 AN: 1461802 Hom.: 10780 Cov.: 32 AF XY: 0.113 AC XY: 82083 AN XY: 727200

Gnomad4 AFR exome AF: 0.0179

Gnomad4 AMR exome AF: 0.0524

Gnomad4 ASJ exome AF: 0.0794

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0357

Gnomad4 FIN exome AF: 0.119

Gnomad4 NFE exome AF: 0.132

Gnomad4 OTH exome AF: 0.103

GnomAD4 genome AF: 0.0864 AC: 13146 AN: 152144 Hom.: 781 Cov.: 32 AF XY: 0.0837 AC XY: 6223 AN XY: 74378

Gnomad4 AFR AF: 0.0220

Gnomad4 AMR AF: 0.0726

Gnomad4 ASJ AF: 0.0735

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0278

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.0825

Alfa AF: 0.116 Hom.: 1867

Bravo AF: 0.0799

TwinsUK AF: 0.144 AC: 533

ALSPAC AF: 0.127 AC: 491

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.133 AC: 1144

ExAC AF: 0.0884 AC: 10728

Asia WGS AF: 0.0220 AC: 77 AN: 3478

EpiCase AF: 0.125

EpiControl AF: 0.128

ClinVar

Significance: Conflicting classifications of pathogenicity; other

Submissions summary: Uncertain:2 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 1631143, 33250842, 21228398, 20981092) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 07, 2018	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Muscle AMP deaminase deficiency Uncertain:1 Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	Jan 06, 2021	The p.Pro81Leu variant in the AMPD1 gene has been previously reported in 11 unrelated individuals with reported AMPD deficiency (Morisaki et al., 1992). Of note, all individuals were homozygous for this variant as well as the p.Gln45* variant. The highest allele frequency of the p.Pro81Leu variant was identified in the European population at 17,214/129,128 chromosomes (13.33%) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools predict that the p.Pro81Leu 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.Pro81Leu variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PP3] -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 06, 2020	- -

AMPD1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	5.7e-12	P;P;P
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.012	D;D
Vest4		0.32
MPC		0.46
ClinPred		0.028	T
GERP RS		5.6
Varity_R		0.66
gMVP		0.69

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: rs61752479; hg19: chr1-115231254; COSMIC: COSV62415390; COSMIC: COSV62415390;