rs397514744

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_022114.4(PRDM16):c.872C>T(p.Pro291Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000392 in 1,606,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

PRDM16
NM_022114.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:4

Conservation

PhyloP100: 7.66

Publications

5 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: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.767

BS2

High AC in GnomAdExome4 at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM16	NM_022114.4 link	c.872C>T	p.Pro291Leu	missense_variant	Exon 6 of 17	ENST00000270722.10	NP_071397.3	Q9HAZ2-1
PRDM16	NM_199454.3 link	c.872C>T	p.Pro291Leu	missense_variant	Exon 6 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.872C>T	p.Pro291Leu	missense_variant	Exon 6 of 17	1	NM_022114.4	ENSP00000270722.5		Q9HAZ2-1

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

149296

Hom.:

Cov.:

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000591

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000366

AC:

AN:

245952

AF XY:

0.0000298

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000634

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000405

AC:

AN:

1457266

Hom.:

Cov.:

AF XY:

0.0000414

AC XY:

AN XY:

724678

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33160

American (AMR)

AF:

0.0000448

AC:

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39612

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86038

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52038

Middle Eastern (MID)

AF:

0.000375

AC:

AN:

5336

European-Non Finnish (NFE)

AF:

0.0000477

AC:

AN:

1110158

Other (OTH)

AF:

0.0000166

AC:

AN:

60170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000268

AC:

AN:

149296

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

72950

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39400

American (AMR)

AF:

0.00

AC:

AN:

15104

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000591

AC:

AN:

67630

Other (OTH)

AF:

0.00

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000453

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Left ventricular noncompaction 8

Uncertain:3

Nov 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 291 of the PRDM16 protein (p.Pro291Leu). This variant is present in population databases (rs397514744, gnomAD 0.006%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 23768516). ClinVar contains an entry for this variant (Variation ID: 60728). 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 disruptive. 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. -

Jan 07, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 19, 2023

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.872C>T variant in PRDM16 has previously been reported in one individual with dilated cardiomyopathy and it has been deposited in ClinVar [ClinVar ID: 60728]. The c.872C>T variant is observed in 21 alleles (~0.0036% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases, which may include individuals with cardiac disorders. The c.872C>T variant in PRDM16 is located in exon 6 of this 17-exon gene, and is predicted to replace an evolutionarily conserved proline amino acid with leucine at position 291 (p.(Pro291Leu)) in one of the zinc finger domains (C2H2-type 2; UniProt ID:Q9HAZ2) in the encoded protein. In silico predictions are inconclusive of damaging effect for the p.(Pro291Leu) variant [CADD v1.6 = 25.8, REVEL = 0.306]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.872C>T p.(Pro291Leu) variant identified in PRDM16 is classified as a Variant of Uncertain Significance. -

Cardiomyopathy, dilated, 1LL

Pathogenic:1

Jul 11, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Primary dilated cardiomyopathy

Uncertain:1

Feb 26, 2021

Loeys Lab, Universiteit Antwerpen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change results in a missense variant in the PRDM16 gene (p.(Pro291Leu)). This variant is present in population databases with a prevalence of 9/243160 in GnomAD). The variant has been described before in a DCM patient (PMID:23768516). The variant affects a highly conserved nucleotide and amino acid, located in the Zinc Finger domain (PM1). No functional data are available. Prediction programs predict a pathogenic effect (Polyphen-2-HumDiv: probably damaging; Polyphen-2-HumVar: probably damaging; SIFT: deleterious; Mutation Taster: disease causing) (PP3). The variant was identified in a patient with DCM who carried two additional variants of unknown significance (MYH7 c.1997A>G; JUPc.56C>T). No data on segregation are available. In conclusion this variant was classified as a variant of unknown significance according to ACMG-guidelines (insufficient data, criteria for other classification are not met: PP3, PM1). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.085

T;.;.;D;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.77

D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

.;M;.;M;.

PhyloP100

7.7

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-6.0

D;D;D;D;D

REVEL

Uncertain

0.31

Sift

Benign

0.035

D;D;D;D;D

Sift4G

Uncertain

0.059

T;T;T;T;T

Polyphen

1.0, 1.0

.;D;.;D;.

Vest4

0.77

MVP

0.48

MPC

1.1

ClinPred

0.93

GERP RS

4.3

Varity_R

0.34

gMVP

0.39

Mutation Taster

=52/48

polymorphism

(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