rs870124

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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

Publications

34 publications found

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 Gene-Disease associations (from GenCC):

left ventricular noncompaction 8
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
left ventricular noncompaction
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

PRDM16 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 227026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
PRDM16	NM_022114.4 link	c.1597T>C	p.Ser533Pro	missense_variant	Exon 9 of 17	ENST00000270722.10	NP_071397.3	Q9HAZ2-1
PRDM16	NM_199454.3 link	c.1597T>C	p.Ser533Pro	missense_variant	Exon 9 of 17		NP_955533.2	Q9HAZ2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM16	ENST00000270722.10 link	c.1597T>C	p.Ser533Pro	missense_variant	Exon 9 of 17	1	NM_022114.4	ENSP00000270722.5		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

GnomAD2 exomes

AF:

0.890

AC:

219507

AN:

246742

AF XY:

0.888

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 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

African (AFR)

AF:

0.975

AC:

32631

AN:

33476

American (AMR)

AF:

0.919

AC:

41075

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.851

AC:

22202

AN:

26100

East Asian (EAS)

AF:

1.00

AC:

39678

AN:

39692

South Asian (SAS)

AF:

0.946

AC:

81604

AN:

86220

European-Finnish (FIN)

AF:

0.913

AC:

46930

AN:

51402

Middle Eastern (MID)

AF:

0.904

AC:

5211

AN:

5762

European-Non Finnish (NFE)

AF:

0.828

AC:

920144

AN:

1111604

Other (OTH)

AF:

0.860

AC:

51900

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

11209

22417

33626

44834

56043

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21038

42076

63114

84152

105190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.893

AC:

135751

AN:

152000

Hom.:

60967

Cov.:

AF XY:

0.900

AC XY:

66865

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.970

AC:

40261

AN:

41486

American (AMR)

AF:

0.892

AC:

13641

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.846

AC:

2933

AN:

3468

East Asian (EAS)

AF:

0.999

AC:

5117

AN:

5124

South Asian (SAS)

AF:

0.953

AC:

4582

AN:

4808

European-Finnish (FIN)

AF:

0.916

AC:

9698

AN:

10588

Middle Eastern (MID)

AF:

0.891

AC:

262

AN:

294

European-Non Finnish (NFE)

AF:

0.834

AC:

56653

AN:

67916

Other (OTH)

AF:

0.901

AC:

1897

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

713

1426

2139

2852

3565

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

896

1792

2688

3584

4480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.854

Hom.:

114150

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

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

Sep 09, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Left ventricular noncompaction 8

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

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;.

PhyloP100

2.0

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over