rs2493292

Variant names:

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.1898C>T(p.Pro633Leu) variant causes a missense change. The variant allele was found at a frequency of 0.135 in 1,586,060 control chromosomes in the GnomAD database, including 15,641 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1614 hom., cov: 33)

Exomes 𝑓: 0.13 ( 14027 hom. )

Consequence

PRDM16
NM_022114.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.65

Publications

35 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=0.0017106235).

BP6

Variant 1-3412095-C-T is Benign according to our data. Variant chr1-3412095-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM16	NM_022114.4 link	c.1898C>T	p.Pro633Leu	missense_variant	Exon 9 of 17	ENST00000270722.10	NP_071397.3	Q9HAZ2-1
PRDM16	NM_199454.3 link	c.1898C>T	p.Pro633Leu	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.1898C>T	p.Pro633Leu	missense_variant	Exon 9 of 17	1	NM_022114.4	ENSP00000270722.5		Q9HAZ2-1

Frequencies

GnomAD3 genomes

AF:

0.140

AC:

21321

AN:

151990

Hom.:

1612

Cov.:

show subpopulations

Gnomad AFR

AF:

0.164

Gnomad AMI

AF:

0.0965

Gnomad AMR

AF:

0.115

Gnomad ASJ

AF:

0.214

Gnomad EAS

AF:

0.00931

Gnomad SAS

AF:

0.0720

Gnomad FIN

AF:

0.102

Gnomad MID

AF:

0.237

Gnomad NFE

AF:

0.148

Gnomad OTH

AF:

0.158

GnomAD2 exomes

AF:

0.123

AC:

28161

AN:

228982

AF XY:

0.125

show subpopulations

Gnomad AFR exome

AF:

0.164

Gnomad AMR exome

AF:

0.0802

Gnomad ASJ exome

AF:

0.223

Gnomad EAS exome

AF:

0.0108

Gnomad FIN exome

AF:

0.0988

Gnomad NFE exome

AF:

0.156

Gnomad OTH exome

AF:

0.154

GnomAD4 exome

AF:

0.135

AC:

193548

AN:

1433952

Hom.:

14027

Cov.:

AF XY:

0.134

AC XY:

95216

AN XY:

709876

show subpopulations

African (AFR)

AF:

0.161

AC:

5269

AN:

32678

American (AMR)

AF:

0.0849

AC:

3588

AN:

42262

Ashkenazi Jewish (ASJ)

AF:

0.215

AC:

5239

AN:

24378

East Asian (EAS)

AF:

0.00691

AC:

272

AN:

39356

South Asian (SAS)

AF:

0.0774

AC:

6402

AN:

82666

European-Finnish (FIN)

AF:

0.106

AC:

5455

AN:

51668

Middle Eastern (MID)

AF:

0.244

AC:

1371

AN:

5612

European-Non Finnish (NFE)

AF:

0.144

AC:

157760

AN:

1096364

Other (OTH)

AF:

0.139

AC:

8192

AN:

58968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

10368

20736

31104

41472

51840

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5526

11052

16578

22104

27630

<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:

0.140

AC:

21323

AN:

152108

Hom.:

1614

Cov.:

AF XY:

0.136

AC XY:

10139

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.163

AC:

6776

AN:

41498

American (AMR)

AF:

0.115

AC:

1763

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.214

AC:

744

AN:

3472

East Asian (EAS)

AF:

0.00933

AC:

AN:

5142

South Asian (SAS)

AF:

0.0715

AC:

344

AN:

4814

European-Finnish (FIN)

AF:

0.102

AC:

1087

AN:

10612

Middle Eastern (MID)

AF:

0.238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.148

AC:

10069

AN:

67954

Other (OTH)

AF:

0.158

AC:

334

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

944

1889

2833

3778

4722

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

230

460

690

920

1150

<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:

0.148

Hom.:

7826

Bravo

AF:

0.143

TwinsUK

AF:

0.139

AC:

516

ALSPAC

AF:

0.145

AC:

558

ESP6500AA

AF:

0.154

AC:

659

ESP6500EA

AF:

0.152

AC:

1283

ExAC

AF:

0.126

AC:

15289

Asia WGS

AF:

0.0560

AC:

195

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Apr 10, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 23, 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

- -

Clinical Genetics, Academic Medical Center

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

Pro633Leu in exon 9 of PRDM16: This variant is not expected to have clinical sig nificance because it has been identified in 15.4% (659/4286) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs2493292). -

Left ventricular noncompaction 8

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 11, 2023

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

0.075

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0055

T;.;.;T;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.037

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

D;D;D;D;D

MetaRNN

Benign

0.0017

T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.69

.;N;.;N;.

PhyloP100

4.7

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.23

N;N;N;N;N

REVEL

Benign

0.074

Sift

Uncertain

0.023

D;D;D;D;D

Sift4G

Benign

0.33

T;T;T;T;T

Polyphen

0.066, 0.039

.;B;.;B;.

Vest4

0.076

MPC

0.37

ClinPred

0.016

GERP RS

4.2

Varity_R

0.047

gMVP

0.11

Mutation Taster

=99/1

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