rs587779369

chr1-114677389-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000036.3(AMPD1):c.1350C>G(p.Cys450Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: AMPD1 NM_000036.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.414

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMPD1	NM_000036.3	c.1350C>G	p.Cys450Trp	missense_variant	10/16	ENST00000520113.7
AMPD1	NM_001172626.2	c.1338C>G	p.Cys446Trp	missense_variant	9/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMPD1	ENST00000520113.7	c.1350C>G	p.Cys450Trp	missense_variant	10/16	1	NM_000036.3	P4
AMPD1	ENST00000369538.4	c.1338C>G	p.Cys446Trp	missense_variant	9/15	2		A1
AMPD1	ENST00000639077.1	n.1015C>G		non_coding_transcript_exon_variant	7/13	5
AMPD1	ENST00000637080.1	c.*557C>G		3_prime_UTR_variant, NMD_transcript_variant	8/14	5

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251474 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autism Uncertain:1

Uncertain significance, criteria provided, single submitter

reference population

State Key Lab of Medical Genetics, Central South University

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.70	T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.66
MVP		0.93
MPC		0.43
ClinPred		0.98	D
GERP RS		2.5
Varity_R		0.71
gMVP		0.92

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: rs587779369; hg19: chr1-115220010;