rs187194973

Positions:

Variant summary

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

The NM_022114.4(PRDM16):c.100G>A(p.Ala34Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00288 in 1,612,890 control chromosomes in the GnomAD database, including 12 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. A34V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0030 ( 11 hom. )

Consequence

PRDM16
NM_022114.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.85

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=0.01160112).

BP6

Variant 1-3186187-G-A is Benign according to our data. Variant chr1-3186187-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-3186187-G-A is described in Lovd as [Benign]. Variant chr1-3186187-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 281 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM16	NM_022114.4 linkuse as main transcript	c.100G>A	p.Ala34Thr	missense_variant	2/17	ENST00000270722.10
PRDM16	NM_199454.3 linkuse as main transcript	c.100G>A	p.Ala34Thr	missense_variant	2/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM16	ENST00000270722.10 linkuse as main transcript	c.100G>A	p.Ala34Thr	missense_variant	2/17	1	NM_022114.4	P1	Q9HAZ2-1

Frequencies

GnomAD3 genomes

AF:

0.00185

AC:

281

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00245

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00313

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00178

AC:

440

AN:

247300

Hom.:

AF XY:

0.00178

AC XY:

240

AN XY:

134862

show subpopulations

Gnomad AFR exome

AF:

0.000786

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000335

Gnomad SAS exome

AF:

0.000915

Gnomad FIN exome

AF:

0.00297

Gnomad NFE exome

AF:

0.00282

Gnomad OTH exome

AF:

0.00183

GnomAD4 exome

AF:

0.00299

AC:

4368

AN:

1460548

Hom.:

Cov.:

AF XY:

0.00292

AC XY:

2120

AN XY:

726572

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00114

Gnomad4 FIN exome

AF:

0.00303

Gnomad4 NFE exome

AF:

0.00355

Gnomad4 OTH exome

AF:

0.00225

GnomAD4 genome

AF:

0.00184

AC:

281

AN:

152342

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

135

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000649

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00245

Gnomad4 NFE

AF:

0.00313

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00237

Hom.:

Bravo

AF:

0.00166

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00115

AC:

ESP6500EA

AF:

0.00247

AC:

ExAC

AF:

0.00199

AC:

241

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00284

EpiControl

AF:

0.00207

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 12, 2017	p.Ala34Thr in exon 2 of PRDM16: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (371/125336) of European chro mosomes by the Genome Aggregation Database Sequencing Project (http://gnomad.bro adinstitute.org; dbSNP rs187194973). ACMG/AMP Criteria applied: BA1 (Richards 20 15). -
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	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	PRDM16: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2020	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

Left ventricular noncompaction 8

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

T;.;.;T

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Benign

0.071

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.0

.;M;.;M

MutationTaster

Benign

0.93

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

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.84

N;N;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.0060

D;D;D;D

Sift4G

Benign

0.34

T;T;T;T

Polyphen

0.92, 0.92

.;P;.;P

Vest4

0.50

MVP

0.47

MPC

0.62

ClinPred

0.028

GERP RS

5.1

Varity_R

0.12

gMVP

0.22

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