rs35658696
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2
The NM_001177306.2(PAM):c.1688A>G(p.Asp563Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0422 in 1,599,210 control chromosomes in the GnomAD database, including 1,705 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: 𝑓 0.031 ( 108 hom., cov: 32)
Exomes 𝑓: 0.043 ( 1597 hom. )
Consequence
PAM
NM_001177306.2 missense
NM_001177306.2 missense
Scores
4
10
4
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 8.29
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 Benign. Variant got -12 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.008397847).
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0311 (4731/152258) while in subpopulation NFE AF= 0.0496 (3370/67996). AF 95% confidence interval is 0.0482. There are 108 homozygotes in gnomad4. There are 2277 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd at 108 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAM | NM_001177306.2 | c.1688A>G | p.Asp563Gly | missense_variant | 17/26 | ENST00000438793.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAM | ENST00000438793.8 | c.1688A>G | p.Asp563Gly | missense_variant | 17/26 | 1 | NM_001177306.2 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0311 AC: 4730AN: 152140Hom.: 108 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0312 AC: 7821AN: 250674Hom.: 183 AF XY: 0.0317 AC XY: 4292AN XY: 135474
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GnomAD4 exome AF: 0.0434 AC: 62784AN: 1446952Hom.: 1597 Cov.: 27 AF XY: 0.0424 AC XY: 30587AN XY: 720872
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GnomAD4 genome ? AF: 0.0311 AC: 4731AN: 152258Hom.: 108 Cov.: 32 AF XY: 0.0306 AC XY: 2277AN XY: 74460
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223
ESP6500AA
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33
ESP6500EA
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424
ExAC
?
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3908
Asia WGS
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3476
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ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;.;.;.;.
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;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
Benign
T
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;D;D;D;D
Vest4
MPC
0.75
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