1-114673131-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000036.3(AMPD1):c.2227C>A(p.Leu743Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AMPD1 NM_000036.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.294

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09971848).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMPD1	NM_000036.3	c.2227C>A	p.Leu743Ile	missense_variant	16/16	ENST00000520113.7
AMPD1	NM_001172626.2	c.2215C>A	p.Leu739Ile	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMPD1	ENST00000520113.7	c.2227C>A	p.Leu743Ile	missense_variant	16/16	1	NM_000036.3	P4
AMPD1	ENST00000369538.4	c.2215C>A	p.Leu739Ile	missense_variant	15/15	2		A1
AMPD1	ENST00000637080.1	c.*1434C>A		3_prime_UTR_variant, NMD_transcript_variant	14/14	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2022

The c.2326C>A (p.L776I) alteration is located in exon 16 (coding exon 16) of the AMPD1 gene. This alteration results from a C to A substitution at nucleotide position 2326, causing the leucine (L) at amino acid position 776 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	18
Dann	Benign	0.94
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	0.96	N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.060	N;N
REVEL	Benign	0.12
Sift	Benign	0.24	T;T
Sift4G	Benign	0.33	T;T
Vest4		0.13
MVP		0.64
MPC		0.089
ClinPred		0.12	T
GERP RS		3.5
Varity_R		0.081
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-115215752;