rs397514744

Positions:

chr1-3402986-C-T

Variant summary

Our verdict is Likely benign. Variant got -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

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 Likely_benign. Variant got -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/exons	MANE	UniProt
PRDM16	NM_022114.4 linkuse as main transcript	c.872C>T	p.Pro291Leu	missense_variant	6/17	ENST00000270722.10
PRDM16	NM_199454.3 linkuse as main transcript	c.872C>T	p.Pro291Leu	missense_variant	6/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM16	ENST00000270722.10 linkuse as main transcript	c.872C>T	p.Pro291Leu	missense_variant	6/17	1	NM_022114.4	P1	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

GnomAD3 exomes

AF:

0.0000366

AC:

AN:

245952

Hom.:

AF XY:

0.0000298

AC XY:

AN XY:

134150

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000268

AC:

AN:

149296

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

72950

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000591

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000647

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

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 07, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	May 19, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 30, 2023	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. 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. ClinVar contains an entry for this variant (Variation ID: 60728). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 23768516). This variant is present in population databases (rs397514744, gnomAD 0.006%). 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). -

Cardiomyopathy, dilated, 1LL

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 11, 2013

- -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Loeys Lab, Universiteit Antwerpen

Feb 26, 2021

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

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

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

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

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