1-3412665-G-C

Position:

chr1-3412665-G-C

Variant summary

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

The NM_022114.4(PRDM16):c.2468G>C(p.Arg823Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00373 in 1,524,290 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R823C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0024 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0039 ( 20 hom. )

Consequence

PRDM16
NM_022114.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 6.30

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=0.008830845).

BP6

Variant 1-3412665-G-C is Benign according to our data. Variant chr1-3412665-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 227865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-3412665-G-C is described in Lovd as [Benign]. Variant chr1-3412665-G-C is described in Lovd as [Likely_benign]. Variant chr1-3412665-G-C is described in Lovd as [Likely_pathogenic].

BS2

High AC in GnomAd4 at 363 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM16	NM_022114.4 linkuse as main transcript	c.2468G>C	p.Arg823Pro	missense_variant	9/17	ENST00000270722.10
PRDM16	NM_199454.3 linkuse as main transcript	c.2468G>C	p.Arg823Pro	missense_variant	9/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM16	ENST00000270722.10 linkuse as main transcript	c.2468G>C	p.Arg823Pro	missense_variant	9/17	1	NM_022114.4	P1	Q9HAZ2-1

Frequencies

GnomAD3 genomes

AF:

0.00238

AC:

363

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00419

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00226

AC:

302

AN:

133652

Hom.:

AF XY:

0.00196

AC XY:

144

AN XY:

73440

show subpopulations

Gnomad AFR exome

AF:

0.000629

Gnomad AMR exome

AF:

0.00144

Gnomad ASJ exome

AF:

0.000710

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000325

Gnomad FIN exome

AF:

0.000854

Gnomad NFE exome

AF:

0.00429

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.00388

AC:

5322

AN:

1371966

Hom.:

Cov.:

AF XY:

0.00375

AC XY:

2529

AN XY:

674654

show subpopulations

Gnomad4 AFR exome

AF:

0.000426

Gnomad4 AMR exome

AF:

0.00142

Gnomad4 ASJ exome

AF:

0.000261

Gnomad4 EAS exome

AF:

0.0000556

Gnomad4 SAS exome

AF:

0.000289

Gnomad4 FIN exome

AF:

0.000795

Gnomad4 NFE exome

AF:

0.00464

Gnomad4 OTH exome

AF:

0.00435

GnomAD4 genome

AF:

0.00238

AC:

363

AN:

152324

Hom.:

Cov.:

AF XY:

0.00231

AC XY:

172

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000770

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000847

Gnomad4 NFE

AF:

0.00419

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.000950

Hom.:

Bravo

AF:

0.00257

ESP6500AA

AF:

0.000903

AC:

ESP6500EA

AF:

0.00190

AC:

ExAC

AF:

0.00140

AC:

157

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2016	p.Arg823Pro in exon 9 of PRDM16: This variant is not expected to have clinical significance because it has been identified in 0.7% (64/9174) of European chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/ ; dbSNP rs371654192). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	PRDM16: BS1, BS2 -

Left ventricular noncompaction 8

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.061

T;.;.;D;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.0088

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

.;M;.;M;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.2

D;D;D;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.018

D;D;D;D;D

Polyphen

1.0, 1.0

.;D;.;D;.

Vest4

0.90

MVP

0.35

MPC

1.3

ClinPred

0.016

GERP RS

4.3

Varity_R

0.57

gMVP

0.62

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