rs187194973

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

6
13

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]

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 rank MANE Protein UniProt
PRDM16NM_022114.4 linkc.100G>A p.Ala34Thr missense_variant Exon 2 of 17 ENST00000270722.10 NP_071397.3 Q9HAZ2-1
PRDM16NM_199454.3 linkc.100G>A p.Ala34Thr missense_variant Exon 2 of 17 NP_955533.2 Q9HAZ2-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRDM16ENST00000270722.10 linkc.100G>A p.Ala34Thr missense_variant Exon 2 of 17 1 NM_022114.4 ENSP00000270722.5 Q9HAZ2-1

Frequencies

GnomAD3 genomes
AF:
0.00185
AC:
281
AN:
152224
Hom.:
1
Cov.:
33
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.:
1
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.:
11
Cov.:
31
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.:
1
Cov.:
33
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.:
0
Bravo
AF:
0.00166
TwinsUK
AF:
0.00324
AC:
12
ALSPAC
AF:
0.00285
AC:
11
ESP6500AA
AF:
0.00115
AC:
5
ESP6500EA
AF:
0.00247
AC:
21
ExAC
AF:
0.00199
AC:
241
Asia WGS
AF:
0.000289
AC:
1
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
Aug 19, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 12, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). -

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

- -

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

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:5
Nov 22, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 15, 2020
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PRDM16: BP4, BS1, BS2 -

Left ventricular noncompaction 8 Benign:2
Oct 14, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.084
BayesDel_addAF
Benign
-0.48
T
BayesDel_noAF
Benign
-0.46
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.013
T;.;.;T
Eigen
Uncertain
0.19
Eigen_PC
Benign
0.14
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.90
D;D;D;D
M_CAP
Benign
0.071
D
MetaRNN
Benign
0.012
T;T;T;T
MetaSVM
Benign
-0.79
T
MutationAssessor
Uncertain
2.0
.;M;.;M
PrimateAI
Benign
0.43
T
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
T
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.

Other links and lift over

dbSNP: rs187194973; hg19: chr1-3102751; COSMIC: COSV54588796; API