rs397514743
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The ENST00000270722.10(PRDM16):c.2447A>G(p.Asn816Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000108 in 1,557,728 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. N816N) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 2 hom. )
Consequence
PRDM16
ENST00000270722.10 missense
ENST00000270722.10 missense
Scores
2
5
12
Clinical Significance
Conservation
PhyloP100: 6.87
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=0.03398019).
BS2
High AC in GnomAd4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRDM16 | NM_022114.4 | c.2447A>G | p.Asn816Ser | missense_variant | 9/17 | ENST00000270722.10 | NP_071397.3 | |
PRDM16 | NM_199454.3 | c.2447A>G | p.Asn816Ser | missense_variant | 9/17 | NP_955533.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PRDM16 | ENST00000270722.10 | c.2447A>G | p.Asn816Ser | missense_variant | 9/17 | 1 | NM_022114.4 | ENSP00000270722 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152194Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000267 AC: 48AN: 179652Hom.: 0 AF XY: 0.000339 AC XY: 34AN XY: 100184
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GnomAD4 exome AF: 0.000115 AC: 161AN: 1405416Hom.: 2 Cov.: 36 AF XY: 0.000182 AC XY: 126AN XY: 694118
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152312Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6AN XY: 74484
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Left ventricular noncompaction 8 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 28, 2023 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 816 of the PRDM16 protein (p.Asn816Ser). This variant is present in population databases (rs397514743, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with left ventricular noncompaction or restrictive cardiomyopathy (PMID: 23768516, 31568572). ClinVar contains an entry for this variant (Variation ID: 60726). 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 11, 2013 | - - |
Familial restrictive cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Klaassen Lab, Charite University Medicine Berlin | Jul 03, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;M;.;M;.
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
0.82, 1.0
.;P;.;D;.
Vest4
MutPred
0.27
.;Gain of glycosylation at N816 (P = 0.0029);.;Gain of glycosylation at N816 (P = 0.0029);.;
MVP
MPC
0.36
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