1-3414622-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_022114.4(PRDM16):c.2666C>T(p.Pro889Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000328 in 1,613,262 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P889P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00034 ( 2 hom. )

Consequence

PRDM16
NM_022114.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 7.46

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 -4 ACMG points.

BS2

High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM16	NM_022114.4 link	c.2666C>T	p.Pro889Leu	missense_variant	Exon 10 of 17	ENST00000270722.10	NP_071397.3	Q9HAZ2-1
PRDM16	NM_199454.3 link	c.2666C>T	p.Pro889Leu	missense_variant	Exon 10 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.2666C>T	p.Pro889Leu	missense_variant	Exon 10 of 17	1	NM_022114.4	ENSP00000270722.5		Q9HAZ2-1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.000397

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000179

AC:

AN:

245350

Hom.:

AF XY:

0.000142

AC XY:

AN XY:

133732

show subpopulations

Gnomad AFR exome

AF:

0.0000656

Gnomad AMR exome

AF:

0.000175

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:

0.000310

Gnomad OTH exome

AF:

0.000501

GnomAD4 exome

AF:

0.000337

AC:

493

AN:

1461048

Hom.:

Cov.:

AF XY:

0.000315

AC XY:

229

AN XY:

726860

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000416

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000237

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.000196

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000250

AC:

ESP6500EA

AF:

0.000604

AC:

ExAC

AF:

0.000223

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Dec 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PRDM16 c.2666C>T; p.Pro889Leu variant (rs201814961) is reported in the literature in an individual with Wolff-Parkinson-White syndrome and supraventricular tachycardia (Coban-Akdemir 2020). This variant is reported in ClinVar (Variation ID: 487607) and is found in the general population with an overall allele frequency of 0.02% (49/276,646 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.418). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Coban-Akdemir ZH et al. Wolff-Parkinson-White syndrome: De novo variants and evidence for mutational burden in genes associated with atrial fibrillation. Am J Med Genet A. 2020 Jun;182(6):1387-1399. PMID: 32233023. -

Jan 08, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32233023, 37614113) -

Left ventricular noncompaction 8

Uncertain:2

May 19, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2025

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 889 of the PRDM16 protein (p.Pro889Leu). This variant is present in population databases (rs201814961, gnomAD 0.03%). This missense change has been observed in individual(s) with Wolff‚ÄìParkinson‚ÄìWhite syndrome (PMID: 32233023). ClinVar contains an entry for this variant (Variation ID: 487607). 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. -

Wolff-Parkinson-White pattern

Uncertain:1

Jul 14, 2017

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

This variant was identified in an individual with Wolff-Parkinson-White syndrome -

not specified

Benign:1

Nov 29, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PRDM16 c.2666C>T (p.Pro889Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 1613262 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 6.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in PRDM16 causing Cardiomyopathy phenotype (5e-05). c.2666C>T has been reported in the literature in an individual affected with Wolff-Parkinson-White syndrome without cardiomyopathy (Coban-Akdemir_2020) and an individual affected with sudden death (Rohrer-2023). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported.The following publications have been ascertained in the context of this evaluation (PMID: 32233023, 37614113). ClinVar contains an entry for this variant (Variation ID: 487607). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.080

T;.;.;D;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Uncertain

0.098

MetaRNN

Uncertain

0.52

D;D;D;D;D

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.8

.;L;.;L;.

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.8

D;D;D;D;D

REVEL

Uncertain

0.42

Sift

Benign

0.032

D;D;D;D;T

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

1.0

.;D;.;D;.

Vest4

0.88

MVP

0.52

MPC

0.86

ClinPred

0.60

GERP RS

4.9

Varity_R

0.33

gMVP

0.78

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