NM_022114.4:c.3301G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_022114.4(PRDM16):​c.3301G>A​(p.Val1101Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,614,114 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00079 ( 3 hom., cov: 33)
Exomes 𝑓: 0.0016 ( 43 hom. )

Consequence

PRDM16
NM_022114.4 missense

Scores

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:9

Conservation

PhyloP100: 2.22

Publications

11 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.005124122).
BP6
Variant 1-3430888-G-A is Benign according to our data. Variant chr1-3430888-G-A is described in ClinVar as Benign. ClinVar VariationId is 60727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000794 (121/152342) while in subpopulation SAS AF = 0.0224 (108/4820). AF 95% confidence interval is 0.019. There are 3 homozygotes in GnomAd4. There are 91 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
BS2
High AC in GnomAd4 at 121 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRDM16NM_022114.4 linkc.3301G>A p.Val1101Met missense_variant Exon 15 of 17 ENST00000270722.10 NP_071397.3 Q9HAZ2-1
PRDM16NM_199454.3 linkc.3301G>A p.Val1101Met missense_variant Exon 15 of 17 NP_955533.2 Q9HAZ2-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRDM16ENST00000270722.10 linkc.3301G>A p.Val1101Met missense_variant Exon 15 of 17 1 NM_022114.4 ENSP00000270722.5 Q9HAZ2-1

Frequencies

GnomAD3 genomes
AF:
0.000788
AC:
120
AN:
152224
Hom.:
3
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.0224
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00317
AC:
785
AN:
247326
AF XY:
0.00426
show subpopulations
Gnomad AFR exome
AF:
0.000193
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000556
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000270
Gnomad OTH exome
AF:
0.00149
GnomAD4 exome
AF:
0.00157
AC:
2288
AN:
1461772
Hom.:
43
Cov.:
32
AF XY:
0.00222
AC XY:
1612
AN XY:
727178
show subpopulations
African (AFR)
AF:
0.000239
AC:
8
AN:
33480
American (AMR)
AF:
0.000134
AC:
6
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.000151
AC:
6
AN:
39700
South Asian (SAS)
AF:
0.0242
AC:
2089
AN:
86252
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53340
Middle Eastern (MID)
AF:
0.000693
AC:
4
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000324
AC:
36
AN:
1111994
Other (OTH)
AF:
0.00230
AC:
139
AN:
60386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
144
288
433
577
721
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
30
60
90
120
150
<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:
0.000794
AC:
121
AN:
152342
Hom.:
3
Cov.:
33
AF XY:
0.00122
AC XY:
91
AN XY:
74494
show subpopulations
African (AFR)
AF:
0.000120
AC:
5
AN:
41574
American (AMR)
AF:
0.000196
AC:
3
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000386
AC:
2
AN:
5180
South Asian (SAS)
AF:
0.0224
AC:
108
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10630
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000441
AC:
3
AN:
68036
Other (OTH)
AF:
0.00
AC:
0
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.498
Heterozygous variant carriers
0
6
11
17
22
28
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000175
Hom.:
0
Bravo
AF:
0.000230
ExAC
AF:
0.00353
AC:
428
Asia WGS
AF:
0.0170
AC:
60
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign
Submissions summary: Uncertain:1Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Apr 29, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

p.Val1101Met in exon 15 of PRDM16: This variant is not expected to have clinical significance because it has been identified in 2.6% (422/16468) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs201654872). -

-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

not provided Benign:3
Feb 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

PRDM16: BP4, BS1, BS2 -

Oct 19, 2018
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27896284, 27535533, 24387995, 23768516) -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Left ventricular noncompaction 8 Benign:2
Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:research

The heterozygous p.Val1101Met variant in PRDM16 has been identified in 2 individuals with dilated cardiomyopathy (PMID: 23768516), and has been identified in >2% of South Asian chromosomes and 7 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal dominant dilated cardiomyopathy. -

Cardiomyopathy, dilated, 1LL Uncertain:1
Jul 11, 2013
OMIM
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:literature only

- -

PRDM16-related disorder Benign:1
Jun 20, 2024
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Benign
-0.67
T
BayesDel_noAF
Benign
-0.72
CADD
Benign
17
DANN
Benign
0.82
DEOGEN2
Benign
0.010
T;.;.;T;.
Eigen
Benign
-0.70
Eigen_PC
Benign
-0.65
FATHMM_MKL
Benign
0.44
N
LIST_S2
Benign
0.48
T;T;T;T;T
MetaRNN
Benign
0.0051
T;T;T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
0.69
.;N;.;N;.
PhyloP100
2.2
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-0.40
N;N;N;N;N
REVEL
Benign
0.033
Sift
Benign
0.21
T;T;T;T;T
Sift4G
Benign
0.17
T;T;T;T;T
Polyphen
0.099, 0.81
.;B;.;P;.
Vest4
0.18
MVP
0.16
MPC
0.071
ClinPred
0.0078
T
GERP RS
1.7
Varity_R
0.025
gMVP
0.11
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs201654872; hg19: chr1-3347452; API