chr5-103003091-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_001177306.2(PAM):c.1672A>G(p.Thr558Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,608,350 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )
Consequence
PAM
NM_001177306.2 missense
NM_001177306.2 missense
Scores
1
12
6
Clinical Significance
Conservation
PhyloP100: 5.27
Genes affected
PAM (HGNC:8596): (peptidylglycine alpha-amidating monooxygenase) This gene encodes a multifunctional protein. The encoded preproprotein is proteolytically processed to generate the mature enzyme. This enzyme includes two domains with distinct catalytic activities, a peptidylglycine alpha-hydroxylating monooxygenase (PHM) domain and a peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL) domain. These catalytic domains work sequentially to catalyze the conversion of neuroendocrine peptides to active alpha-amidated products. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.27447575).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAM | NM_001177306.2 | c.1672A>G | p.Thr558Ala | missense_variant | 17/26 | ENST00000438793.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAM | ENST00000438793.8 | c.1672A>G | p.Thr558Ala | missense_variant | 17/26 | 1 | NM_001177306.2 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152178Hom.: 0 Cov.: 32
GnomAD3 genomes
?
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152178
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GnomAD3 exomes AF: 0.0000598 AC: 15AN: 250640Hom.: 0 AF XY: 0.0000664 AC XY: 9AN XY: 135478
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GnomAD4 exome AF: 0.000101 AC: 147AN: 1456172Hom.: 0 Cov.: 27 AF XY: 0.000103 AC XY: 75AN XY: 724836
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GnomAD4 genome ? AF: 0.000125 AC: 19AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74340
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 27, 2023 | The c.1672A>G (p.T558A) alteration is located in exon 16 (coding exon 16) of the PAM gene. This alteration results from a A to G substitution at nucleotide position 1672, causing the threonine (T) at amino acid position 558 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;.;M;M
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D
REVEL
Uncertain
Sift
Benign
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
P;P;P;P;P
Vest4
MVP
MPC
0.58
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at