rs397514744
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_022114.4(PRDM16):c.872C>T(p.Pro291Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000392 in 1,606,562 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: 𝑓 0.000027 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 0 hom. )
Consequence
PRDM16
NM_022114.4 missense
NM_022114.4 missense
Scores
3
8
7
Clinical Significance
Conservation
PhyloP100: 7.66
Genes affected
PRDM16 (HGNC:14000): (PR/SET domain 16) The reciprocal translocation t(1;3)(p36;q21) occurs in a subset of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). This gene is located near the 1p36.3 breakpoint and has been shown to be specifically expressed in the t(1:3)(p36,q21)-positive MDS/AML. The protein encoded by this gene is a zinc finger transcription factor and contains an N-terminal PR domain. The translocation results in the overexpression of a truncated version of this protein that lacks the PR domain, which may play an important role in the pathogenesis of MDS and AML. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.767
BS2
?
High AC in GnomAdExome4 at 59 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRDM16 | NM_022114.4 | c.872C>T | p.Pro291Leu | missense_variant | 6/17 | ENST00000270722.10 | |
PRDM16 | NM_199454.3 | c.872C>T | p.Pro291Leu | missense_variant | 6/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRDM16 | ENST00000270722.10 | c.872C>T | p.Pro291Leu | missense_variant | 6/17 | 1 | NM_022114.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000268 AC: 4AN: 149296Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000366 AC: 9AN: 245952Hom.: 0 AF XY: 0.0000298 AC XY: 4AN XY: 134150
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GnomAD4 exome AF: 0.0000405 AC: 59AN: 1457266Hom.: 0 Cov.: 32 AF XY: 0.0000414 AC XY: 30AN XY: 724678
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GnomAD4 genome ? AF: 0.0000268 AC: 4AN: 149296Hom.: 0 Cov.: 33 AF XY: 0.0000137 AC XY: 1AN XY: 72950
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Left ventricular noncompaction 8 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 07, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | May 19, 2023 | The c.872C>T variant in PRDM16 has previously been reported in one individual with dilated cardiomyopathy and it has been deposited in ClinVar [ClinVar ID: 60728]. The c.872C>T variant is observed in 21 alleles (~0.0036% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases, which may include individuals with cardiac disorders. The c.872C>T variant in PRDM16 is located in exon 6 of this 17-exon gene, and is predicted to replace an evolutionarily conserved proline amino acid with leucine at position 291 (p.(Pro291Leu)) in one of the zinc finger domains (C2H2-type 2; UniProt ID:Q9HAZ2) in the encoded protein. In silico predictions are inconclusive of damaging effect for the p.(Pro291Leu) variant [CADD v1.6 = 25.8, REVEL = 0.306]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.872C>T p.(Pro291Leu) variant identified in PRDM16 is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 30, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 60728). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 23768516). This variant is present in population databases (rs397514744, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 291 of the PRDM16 protein (p.Pro291Leu). - |
Cardiomyopathy, dilated, 1LL Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 11, 2013 | - - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Loeys Lab, Universiteit Antwerpen | Feb 26, 2021 | This sequence change results in a missense variant in the PRDM16 gene (p.(Pro291Leu)). This variant is present in population databases with a prevalence of 9/243160 in GnomAD). The variant has been described before in a DCM patient (PMID:23768516). The variant affects a highly conserved nucleotide and amino acid, located in the Zinc Finger domain (PM1). No functional data are available. Prediction programs predict a pathogenic effect (Polyphen-2-HumDiv: probably damaging; Polyphen-2-HumVar: probably damaging; SIFT: deleterious; Mutation Taster: disease causing) (PP3). The variant was identified in a patient with DCM who carried two additional variants of unknown significance (MYH7 c.1997A>G; JUPc.56C>T). No data on segregation are available. In conclusion this variant was classified as a variant of unknown significance according to ACMG-guidelines (insufficient data, criteria for other classification are not met: PP3, PM1). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Uncertain
Sift
Benign
D;D;D;D;D
Sift4G
Uncertain
T;T;T;T;T
Polyphen
1.0, 1.0
.;D;.;D;.
Vest4
MVP
MPC
1.1
ClinPred
D
GERP RS
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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