rs870124

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022114.4(PRDM16):c.1597T>C(p.Ser533Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.855 in 1,611,306 control chromosomes in the GnomAD database, including 590,885 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S533L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.89 ( 60967 hom., cov: 30)

Exomes 𝑓: 0.85 ( 529918 hom. )

Consequence

PRDM16
NM_022114.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.03

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]

PRDM16 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.779954E-7).

BP6

Variant 1-3411794-T-C is Benign according to our data. Variant chr1-3411794-T-C is described in ClinVar as [Benign]. Clinvar id is 227026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-3411794-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM16	NM_022114.4 linkuse as main transcript	c.1597T>C	p.Ser533Pro	missense_variant	9/17	ENST00000270722.10
PRDM16	NM_199454.3 linkuse as main transcript	c.1597T>C	p.Ser533Pro	missense_variant	9/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM16	ENST00000270722.10 linkuse as main transcript	c.1597T>C	p.Ser533Pro	missense_variant	9/17	1	NM_022114.4	P1	Q9HAZ2-1

Frequencies

GnomAD3 genomes

AF:

0.893

AC:

135624

AN:

151882

Hom.:

60900

Cov.:

show subpopulations

Gnomad AFR

AF:

0.970

Gnomad AMI

AF:

0.775

Gnomad AMR

AF:

0.891

Gnomad ASJ

AF:

0.846

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.954

Gnomad FIN

AF:

0.916

Gnomad MID

AF:

0.880

Gnomad NFE

AF:

0.834

Gnomad OTH

AF:

0.900

GnomAD3 exomes

AF:

0.890

AC:

219507

AN:

246742

Hom.:

97999

AF XY:

0.888

AC XY:

119089

AN XY:

134044

show subpopulations

Gnomad AFR exome

AF:

0.973

Gnomad AMR exome

AF:

0.923

Gnomad ASJ exome

AF:

0.853

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.950

Gnomad FIN exome

AF:

0.913

Gnomad NFE exome

AF:

0.835

Gnomad OTH exome

AF:

0.869

GnomAD4 exome

AF:

0.851

AC:

1241375

AN:

1459306

Hom.:

529918

Cov.:

AF XY:

0.853

AC XY:

619472

AN XY:

726020

show subpopulations

Gnomad4 AFR exome

AF:

0.975

Gnomad4 AMR exome

AF:

0.919

Gnomad4 ASJ exome

AF:

0.851

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.946

Gnomad4 FIN exome

AF:

0.913

Gnomad4 NFE exome

AF:

0.828

Gnomad4 OTH exome

AF:

0.860

GnomAD4 genome

AF:

0.893

AC:

135751

AN:

152000

Hom.:

60967

Cov.:

AF XY:

0.900

AC XY:

66865

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.970

Gnomad4 AMR

AF:

0.892

Gnomad4 ASJ

AF:

0.846

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.953

Gnomad4 FIN

AF:

0.916

Gnomad4 NFE

AF:

0.834

Gnomad4 OTH

AF:

0.901

Alfa

AF:

0.848

Hom.:

73649

Bravo

AF:

0.892

TwinsUK

AF:

0.838

AC:

3107

ALSPAC

AF:

0.841

AC:

3240

ESP6500AA

AF:

0.967

AC:

3759

ESP6500EA

AF:

0.836

AC:

6902

ExAC

AF:

0.890

AC:

107324

Asia WGS

AF:

0.978

AC:

3401

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ser533Pro in exon 9 of PRDM16: This variant is not expected to have clinical sig nificance because it has been identified in 16.4% (1358/8260) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs870124). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2016	This 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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Left ventricular noncompaction 8

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.83

CADD

Benign

DANN

Benign

0.66

DEOGEN2

Benign

0.0039

T;.;.;T;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.43

T;T;T;T;T

MetaRNN

Benign

5.8e-7

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.7

.;N;.;N;.

MutationTaster

Benign

0.91

P;P;P;P;P;P;P;P

PrimateAI

Uncertain

0.62

PROVEAN

Benign

1.3

N;N;N;N;N

REVEL

Benign

0.089

Sift

Benign

0.65

T;T;T;T;T

Sift4G

Benign

0.45

T;T;T;T;T

Polyphen

0.0

.;B;.;B;.

Vest4

0.035

MPC

0.44

ClinPred

0.0027

GERP RS

5.3

Varity_R

0.096

gMVP

0.30

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over