NM_022114.4:c.2798G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_022114.4(PRDM16):c.2798G>A(p.Arg933Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000885 in 1,468,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R933W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

PRDM16
NM_022114.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.44

Publications

0 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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2664765).

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM16	NM_022114.4 link	c.2798G>A	p.Arg933Gln	missense_variant	Exon 11 of 17	ENST00000270722.10	NP_071397.3
PRDM16	NM_199454.3 link	c.2798G>A	p.Arg933Gln	missense_variant	Exon 11 of 17		NP_955533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM16	ENST00000270722.10 link	c.2798G>A	p.Arg933Gln	missense_variant	Exon 11 of 17	1	NM_022114.4	ENSP00000270722.5

Frequencies

GnomAD3 genomes

AF:

0.0000139

AC:

AN:

143866

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000255

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000693

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000124

AC:

AN:

242070

AF XY:

0.00000759

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000831

AC:

AN:

1324178

Hom.:

Cov.:

AF XY:

0.00000455

AC XY:

AN XY:

659142

show subpopulations

African (AFR)

AF:

0.000101

AC:

AN:

29618

American (AMR)

AF:

0.00

AC:

AN:

39554

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21692

East Asian (EAS)

AF:

0.00

AC:

AN:

31108

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83364

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5156

European-Non Finnish (NFE)

AF:

0.00000685

AC:

AN:

1021814

Other (OTH)

AF:

0.00

AC:

AN:

51770

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.0000139

AC:

AN:

143960

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70036

show subpopulations

African (AFR)

AF:

0.0000254

AC:

AN:

39316

American (AMR)

AF:

0.0000692

AC:

AN:

14452

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3402

East Asian (EAS)

AF:

0.00

AC:

AN:

4464

South Asian (SAS)

AF:

0.00

AC:

AN:

4072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9238

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65832

Other (OTH)

AF:

0.00

AC:

AN:

2016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Left ventricular noncompaction 8

Uncertain:1

Jul 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 933 of the PRDM16 protein (p.Arg933Gln). This variant is present in population databases (rs572092688, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PRDM16-related conditions. ClinVar contains an entry for this variant (Variation ID: 576146). 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 tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.015

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.022

T;.;.;T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.27

T;T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.5

.;M;.;M;.

PhyloP100

9.4

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.9

N;N;N;N;N

REVEL

Benign

0.20

Sift

Uncertain

0.0050

D;D;D;D;D

Sift4G

Benign

0.10

T;T;T;T;T

Polyphen

0.96, 1.0

.;D;.;D;.

Vest4

0.80

MutPred

0.21

.;Loss of methylation at R933 (P = 0.04);Loss of methylation at R933 (P = 0.04);Loss of methylation at R933 (P = 0.04);.;

MVP

0.61

MPC

0.71

ClinPred

0.82

GERP RS

4.6

Varity_R

0.28

gMVP

0.64

Mutation Taster

=69/31

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over