rs376567517

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_022114.4(PRDM16):ā€‹c.553A>Gā€‹(p.Met185Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000861 in 1,613,648 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00052 ( 1 hom., cov: 33)
Exomes š‘“: 0.000041 ( 0 hom. )

Consequence

PRDM16
NM_022114.4 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.54
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 -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.016035497).
BP6
Variant 1-3385266-A-G is Benign according to our data. Variant chr1-3385266-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235271.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr1-3385266-A-G is described in Lovd as [Benign].
BS2
High AC in GnomAd4 at 79 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PRDM16NM_022114.4 linkuse as main transcriptc.553A>G p.Met185Val missense_variant 4/17 ENST00000270722.10 NP_071397.3
PRDM16NM_199454.3 linkuse as main transcriptc.553A>G p.Met185Val missense_variant 4/17 NP_955533.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PRDM16ENST00000270722.10 linkuse as main transcriptc.553A>G p.Met185Val missense_variant 4/171 NM_022114.4 ENSP00000270722 P1Q9HAZ2-1

Frequencies

GnomAD3 genomes
AF:
0.000519
AC:
79
AN:
152176
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00179
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.000140
AC:
35
AN:
249172
Hom.:
1
AF XY:
0.0000887
AC XY:
12
AN XY:
135318
show subpopulations
Gnomad AFR exome
AF:
0.00175
Gnomad AMR exome
AF:
0.000203
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000411
AC:
60
AN:
1461354
Hom.:
0
Cov.:
32
AF XY:
0.0000289
AC XY:
21
AN XY:
726956
show subpopulations
Gnomad4 AFR exome
AF:
0.00116
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.000132
GnomAD4 genome
AF:
0.000519
AC:
79
AN:
152294
Hom.:
1
Cov.:
33
AF XY:
0.000510
AC XY:
38
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.00178
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.000265
Hom.:
0
Bravo
AF:
0.000601
ESP6500AA
AF:
0.000703
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000140
AC:
17
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxApr 10, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJan 11, 2016- -
PRDM16-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 31, 2024This 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
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 11, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
13
DANN
Benign
0.74
DEOGEN2
Benign
0.012
T;.;.;T;.
Eigen
Benign
-0.37
Eigen_PC
Benign
-0.18
FATHMM_MKL
Benign
0.51
D
LIST_S2
Benign
0.66
T;T;T;T;T
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.016
T;T;T;T;T
MetaSVM
Benign
-0.86
T
MutationAssessor
Benign
0.0
.;N;.;N;.
MutationTaster
Benign
1.0
D;N;N;N;N;N;N;N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.44
N;N;N;N;.
REVEL
Benign
0.13
Sift
Benign
0.50
T;T;T;T;.
Sift4G
Benign
0.52
T;T;T;T;T
Polyphen
0.0010, 0.0
.;B;.;B;.
Vest4
0.15
MVP
0.54
MPC
0.36
ClinPred
0.043
T
GERP RS
3.3
Varity_R
0.18
gMVP
0.31

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: rs376567517; hg19: chr1-3301830; COSMIC: COSV54604073; API