rs375887892
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 5P and 7B. PM1PM2PP3BP4_ModerateBP6BS1
The NM_021619.3(PRDM12):c.607G>A(p.Gly203Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000768 in 1,613,622 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000074 ( 0 hom. )
Consequence
PRDM12
NM_021619.3 missense
NM_021619.3 missense
Scores
9
4
6
Clinical Significance
Conservation
PhyloP100: 8.93
Genes affected
PRDM12 (HGNC:13997): (PR/SET domain 12) This gene encodes a transcriptional regulator of sensory neuronal specification that plays a critical role in pain perception. The encoded protein contains an N-terminal PRDI-BF1 and RIZ homology (PR) domain, a SET domain, and three C-terminal C2H2 zinc finger DNA-binding domains. Naturally occurring mutations in this gene are associated with congenital insensitivity to pain (CIP), and hereditary sensory and autonomic neuropathies (HSAN's) affecting peripheral sensory and autonomic neurons. Deregulation of this gene is associated with solid cancers and hematological malignancies including chronic myeloid leukaemia. [provided by RefSeq, Mar 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM1
?
In a domain SET (size 117) in uniprot entity PRD12_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_021619.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN [when BayesDel_addAF, max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]
BP4
?
Computational evidence support a benign effect (MetaRNN=0.19111723).
BP6
?
Variant 9-130678565-G-A is Benign according to our data. Variant chr9-130678565-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 582663.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000105 (16/152198) while in subpopulation EAS AF= 0.00214 (11/5148). AF 95% confidence interval is 0.0012. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRDM12 | NM_021619.3 | c.607G>A | p.Gly203Arg | missense_variant | 4/5 | ENST00000253008.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRDM12 | ENST00000253008.3 | c.607G>A | p.Gly203Arg | missense_variant | 4/5 | 1 | NM_021619.3 | P1 | |
PRDM12 | ENST00000676323.1 | c.607G>A | p.Gly203Arg | missense_variant | 4/6 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152080Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000167 AC: 42AN: 250942Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135662
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GnomAD4 exome AF: 0.0000739 AC: 108AN: 1461424Hom.: 0 Cov.: 29 AF XY: 0.0000922 AC XY: 67AN XY: 727068
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GnomAD4 genome ? AF: 0.000105 AC: 16AN: 152198Hom.: 0 Cov.: 31 AF XY: 0.0000672 AC XY: 5AN XY: 74414
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 02, 2020 | The p.G203R variant (also known as c.607G>A), located in coding exon 4 of the PRDM12 gene, results from a G to A substitution at nucleotide position 607. The glycine at codon 203 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Congenital insensitivity to pain-hypohidrosis syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of loop (P = 0.1242);
MVP
MPC
ClinPred
T
GERP RS
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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