rs201904226

Positions:

chr1-3412649-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_022114.4(PRDM16):c.2452G>A(p.Gly818Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,548,246 control chromosomes in the GnomAD database, including 11 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G818G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 10 hom. )

Consequence

PRDM16
NM_022114.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.02

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070410073).

BP6

Variant 1-3412649-G-A is Benign according to our data. Variant chr1-3412649-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-3412649-G-A is described in Lovd as [Benign]. Variant chr1-3412649-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 248 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM16	NM_022114.4 link	c.2452G>A	p.Gly818Ser	missense_variant	9/17	ENST00000270722.10	NP_071397.3	Q9HAZ2-1
PRDM16	NM_199454.3 link	c.2452G>A	p.Gly818Ser	missense_variant	9/17		NP_955533.2	Q9HAZ2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM16	ENST00000270722.10 link	c.2452G>A	p.Gly818Ser	missense_variant	9/17	1	NM_022114.4	ENSP00000270722.5		Q9HAZ2-1

Frequencies

GnomAD3 genomes

AF:

0.00163

AC:

248

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00273

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00202

AC:

333

AN:

164862

Hom.:

AF XY:

0.00213

AC XY:

195

AN XY:

91746

show subpopulations

Gnomad AFR exome

AF:

0.000421

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00319

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00236

Gnomad FIN exome

AF:

0.000984

Gnomad NFE exome

AF:

0.00276

Gnomad OTH exome

AF:

0.00285

GnomAD4 exome

AF:

0.00211

AC:

2951

AN:

1395908

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

1512

AN XY:

688622

show subpopulations

Gnomad4 AFR exome

AF:

0.000193

Gnomad4 AMR exome

AF:

0.00109

Gnomad4 ASJ exome

AF:

0.00296

Gnomad4 EAS exome

AF:

0.0000812

Gnomad4 SAS exome

AF:

0.00246

Gnomad4 FIN exome

AF:

0.00104

Gnomad4 NFE exome

AF:

0.00229

Gnomad4 OTH exome

AF:

0.00183

GnomAD4 genome

AF:

0.00163

AC:

248

AN:

152338

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00248

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00273

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00199

Hom.:

Bravo

AF:

0.00167

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00197

AC:

ExAC

AF:

0.00186

AC:

211

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PRDM16: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2021	This variant is associated with the following publications: (PMID: 28642161, 30847666) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 12, 2017	p.Gly818Ser in exon 9 of PRDM16: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (21/6980) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst itute.org; dbSNP rs201904226). ACMG/AMP Criteria applied: BA1 (Richards 2015). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 30, 2023	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

PRDM16-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 05, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Left ventricular noncompaction 8

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.56

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0029

T;.;.;T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.51

T;T;T;T;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.0070

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

.;L;.;L;.

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.62

N;N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.34

T;T;T;T;T

Sift4G

Benign

0.71

T;T;T;T;T

Polyphen

1.0

.;D;.;D;.

Vest4

0.21

MVP

0.61

MPC

0.53

ClinPred

0.028

GERP RS

3.4

Varity_R

0.032

gMVP

0.36

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