chr1-114684278-C-A

Position:

• chr1-114684278-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_000036.3(AMPD1):​c.468G>T​(p.Gln156His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000777 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. Q156K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (0 hom.)
• Consequence: AMPD1 NM_000036.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:2
• Conservation: PhyloP100: 2.08

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-114684278-C-A is Pathogenic according to our data. Variant chr1-114684278-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197620.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=5}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2525351). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMPD1	NM_000036.3	c.468G>T	p.Gln156His	missense_variant	5/16	ENST00000520113.7	NP_000027.3
AMPD1	NM_001172626.2	c.456G>T	p.Gln152His	missense_variant	4/15		NP_001166097.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMPD1	ENST00000520113.7	c.468G>T	p.Gln156His	missense_variant	5/16	1	NM_000036.3	ENSP00000430075.3

Frequencies

GnomAD3 genomes AF: 0.000888 AC: 135 AN: 152066 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000537 AC: 135 AN: 251484 Hom.: 0 AF XY: 0.000559 AC XY: 76 AN XY: 135918

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000914

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000765 AC: 1119 AN: 1461894 Hom.: 0 Cov.: 30 AF XY: 0.000756 AC XY: 550 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000941

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.000888 AC: 135 AN: 152066 Hom.: 0 Cov.: 32 AF XY: 0.000956 AC XY: 71 AN XY: 74278

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.000827

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000445 AC: 54

EpiCase AF: 0.00136

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	AMPD1: PM3:Very Strong, PM2, PS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2023	Reported previously (as Q156H due to alternate nomenclature) in multiple individuals with MADA deficiency and myopathy who were compound heterozygous for the Q189H variant and the most common AMPD1 variant, Q45X (Gross et al., 2002; Neroldova et al., 2016; Rannou et al., 2017); Published functional studies demonstrate altered enzyme activity (Gross et al., 2002); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27296017, 12117480, 29095874, 34426522, 31980526, 32483371, 34269512) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2015	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The AMPD1 p.Q189H variant was identified in the literature as a compound heterozygous variant in 10 individuals with myoadenylate deaminase deficiency (Gross_2002_PMID_12117480). The variant was identified in dbSNP (ID: rs139582106) and ClinVar (classified as likely pathogenic by EGL Genetic Diagnostics, Fulgent Genetics and GeneDx; classified as uncertain significance by Invitae). The variant was identified in control databases in 147 of 282856 chromosomes at a frequency of 0.0005197 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 115 of 129180 chromosomes (freq: 0.00089), Latino in 25 of 35440 chromosomes (freq: 0.000705), Other in 3 of 7226 chromosomes (freq: 0.000415), African in 2 of 24958 chromosomes (freq: 0.00008) and European (Finnish) in 2 of 25120 chromosomes (freq: 0.00008), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Q189 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional studies have demonstrated altered enzymatic activity from the p.Q189H variant compared to wildtype (Gross_2002_PMID_12117480). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Muscle AMP deaminase deficiency Pathogenic:3 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 31, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 24, 2020	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4_MOD,PM2. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 189 of the AMPD1 protein (p.Gln189His). This variant is present in population databases (rs139582106, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with myoadenylate deaminase deficiency (PMID: 12117480, 19353846, 29095874). This variant is also known as G468T (Q156H). ClinVar contains an entry for this variant (Variation ID: 197620). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects AMPD1 function (PMID: 12117480). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Benign	0.72
DEOGEN2	Benign	0.40	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.16
Sift	Benign	0.28	T;T
Sift4G	Benign	0.30	T;T
Vest4		0.79
MVP		0.45
MPC		0.41
ClinPred		0.81	D
GERP RS		2.9
Varity_R		0.12
gMVP		0.94

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: rs139582106; hg19: chr1-115226899; COSMIC: COSV100815393;