rs369539275

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The ENST00000270722.10(PRDM16):​c.109G>A​(p.Glu37Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,612,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

PRDM16
ENST00000270722.10 missense

Scores

10
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.07
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PRDM16NM_022114.4 linkuse as main transcriptc.109G>A p.Glu37Lys missense_variant 2/17 ENST00000270722.10 NP_071397.3
PRDM16NM_199454.3 linkuse as main transcriptc.109G>A p.Glu37Lys missense_variant 2/17 NP_955533.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PRDM16ENST00000270722.10 linkuse as main transcriptc.109G>A p.Glu37Lys missense_variant 2/171 NM_022114.4 ENSP00000270722 P1Q9HAZ2-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152214
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000323
AC:
8
AN:
247394
Hom.:
0
AF XY:
0.0000371
AC XY:
5
AN XY:
134848
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000167
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000269
Gnomad OTH exome
AF:
0.000332
GnomAD4 exome
AF:
0.0000164
AC:
24
AN:
1460548
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
726566
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000126
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152214
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000264
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000118
AC:
1
ExAC
AF:
0.0000248
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 20, 2022The PRDM16 c.109G>A; p.Glu37Lys variant (rs369539275), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 576283). This variant is found in the general population with an overall allele frequency of 0.003% (9/278766 alleles) in the Genome Aggregation Database. The glutamic acid at codon 37 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.182). Due to limited information, the clinical significance of the PRDM16 variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 29, 2020Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 576283; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function -
Left ventricular noncompaction 8 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 23, 2023This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 37 of the PRDM16 protein (p.Glu37Lys). This variant is present in population databases (rs369539275, gnomAD 0.02%). 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: 576283). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.37
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.022
T;.;.;T
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.95
D;D;D;D
M_CAP
Benign
0.054
D
MetaRNN
Uncertain
0.52
D;D;D;D
MetaSVM
Benign
-0.96
T
MutationAssessor
Uncertain
2.0
.;M;.;M
MutationTaster
Benign
0.99
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-1.2
N;N;N;N
REVEL
Benign
0.18
Sift
Uncertain
0.013
D;D;D;D
Sift4G
Uncertain
0.056
T;D;T;D
Polyphen
0.99, 0.98
.;D;.;D
Vest4
0.63
MVP
0.39
MPC
0.46
ClinPred
0.19
T
GERP RS
4.2
Varity_R
0.16
gMVP
0.44

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs369539275; hg19: chr1-3102760; COSMIC: COSV54586248; API