rs201807364
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_022114.4(PRDM16):c.2126T>C(p.Met709Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000044 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
PRDM16
NM_022114.4 missense
NM_022114.4 missense
Scores
2
16
Clinical Significance
Conservation
PhyloP100: 4.98
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 Benign. Variant got -8 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.040723056).
BS2
?
High AC in GnomAd4 at 34 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRDM16 | NM_022114.4 | c.2126T>C | p.Met709Thr | missense_variant | 9/17 | ENST00000270722.10 | |
PRDM16 | NM_199454.3 | c.2126T>C | p.Met709Thr | missense_variant | 9/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRDM16 | ENST00000270722.10 | c.2126T>C | p.Met709Thr | missense_variant | 9/17 | 1 | NM_022114.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000223 AC: 34AN: 152210Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000723 AC: 18AN: 249056Hom.: 0 AF XY: 0.0000887 AC XY: 12AN XY: 135226
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GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461496Hom.: 0 Cov.: 36 AF XY: 0.0000289 AC XY: 21AN XY: 727062
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GnomAD4 genome ? AF: 0.000223 AC: 34AN: 152328Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18AN XY: 74482
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Left ventricular noncompaction 8 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 06, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 709 of the PRDM16 protein (p.Met709Thr). This variant is present in population databases (rs201807364, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PRDM16-related conditions. ClinVar contains an entry for this variant (Variation ID: 426184). 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 tolerated. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 23, 2022 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N
REVEL
Benign
Sift
Benign
T;T;T;T;T
Sift4G
Benign
T;T;T;T;T
Polyphen
0.33, 0.094
.;B;.;B;.
Vest4
MVP
MPC
0.44
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