rs371654192

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM5BP4_StrongBP6_Very_StrongBS2

The NM_022114.4(PRDM16):​c.2468G>A​(p.Arg823His) variant causes a missense change. The variant allele was found at a frequency of 0.000251 in 1,524,294 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R823C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00023 ( 2 hom. )

Consequence

PRDM16
NM_022114.4 missense

Scores

1
8
9

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 6.30
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 Benign. Variant got -14 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-3412665-G-C is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.00794363).
BP6
Variant 1-3412665-G-A is Benign according to our data. Variant chr1-3412665-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 510913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-3412665-G-A is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PRDM16NM_022114.4 linkuse as main transcriptc.2468G>A p.Arg823His missense_variant 9/17 ENST00000270722.10
PRDM16NM_199454.3 linkuse as main transcriptc.2468G>A p.Arg823His missense_variant 9/17

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PRDM16ENST00000270722.10 linkuse as main transcriptc.2468G>A p.Arg823His missense_variant 9/171 NM_022114.4 P1Q9HAZ2-1

Frequencies

GnomAD3 genomes
AF:
0.000401
AC:
61
AN:
152208
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00103
Gnomad FIN
AF:
0.00461
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000471
AC:
63
AN:
133652
Hom.:
0
AF XY:
0.000572
AC XY:
42
AN XY:
73440
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000479
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00125
Gnomad FIN exome
AF:
0.00332
Gnomad NFE exome
AF:
0.0000712
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000234
AC:
321
AN:
1371968
Hom.:
2
Cov.:
36
AF XY:
0.000274
AC XY:
185
AN XY:
674654
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000308
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000278
Gnomad4 SAS exome
AF:
0.00113
Gnomad4 FIN exome
AF:
0.00377
Gnomad4 NFE exome
AF:
0.0000524
Gnomad4 OTH exome
AF:
0.000177
GnomAD4 genome
AF:
0.000400
AC:
61
AN:
152326
Hom.:
0
Cov.:
33
AF XY:
0.000591
AC XY:
44
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00103
Gnomad4 FIN
AF:
0.00461
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000219
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.000490
AC:
55
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxJul 19, 2017This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Left ventricular noncompaction 8 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeDec 27, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.38
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.022
T;.;.;T;.
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D
MetaRNN
Benign
0.0079
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.4
.;M;.;M;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-2.2
N;N;N;N;N
REVEL
Benign
0.13
Sift
Uncertain
0.0010
D;D;D;D;D
Sift4G
Uncertain
0.0080
D;D;D;D;D
Polyphen
1.0, 1.0
.;D;.;D;.
Vest4
0.65
MVP
0.57
MPC
1.2
ClinPred
0.11
T
GERP RS
4.3
Varity_R
0.20
gMVP
0.53

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: rs371654192; hg19: chr1-3329229; API