rs397514743

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000270722.10(PRDM16):​c.2447A>G​(p.Asn816Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000108 in 1,557,728 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. N816N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 2 hom. )

Consequence

PRDM16
ENST00000270722.10 missense

Scores

2
5
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 6.87
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 -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.03398019).
BS2
High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PRDM16NM_022114.4 linkuse as main transcriptc.2447A>G p.Asn816Ser missense_variant 9/17 ENST00000270722.10 NP_071397.3
PRDM16NM_199454.3 linkuse as main transcriptc.2447A>G p.Asn816Ser missense_variant 9/17 NP_955533.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PRDM16ENST00000270722.10 linkuse as main transcriptc.2447A>G p.Asn816Ser missense_variant 9/171 NM_022114.4 ENSP00000270722 P1Q9HAZ2-1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152194
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00103
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000267
AC:
48
AN:
179652
Hom.:
0
AF XY:
0.000339
AC XY:
34
AN XY:
100184
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00195
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000224
GnomAD4 exome
AF:
0.000115
AC:
161
AN:
1405416
Hom.:
2
Cov.:
36
AF XY:
0.000182
AC XY:
126
AN XY:
694118
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000267
Gnomad4 SAS exome
AF:
0.00187
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000185
Gnomad4 OTH exome
AF:
0.000121
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152312
Hom.:
0
Cov.:
33
AF XY:
0.0000806
AC XY:
6
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00103
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000108
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.000264
AC:
30
Asia WGS
AF:
0.00144
AC:
5
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Left ventricular noncompaction 8 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 28, 2023This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 816 of the PRDM16 protein (p.Asn816Ser). This variant is present in population databases (rs397514743, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with left ventricular noncompaction or restrictive cardiomyopathy (PMID: 23768516, 31568572). ClinVar contains an entry for this variant (Variation ID: 60726). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 11, 2013- -
Familial restrictive cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterresearchKlaassen Lab, Charite University Medicine BerlinJul 03, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.57
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.011
T;.;.;T;.
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.86
D;D;D;D;D
M_CAP
Pathogenic
0.56
D
MetaRNN
Benign
0.034
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.5
.;M;.;M;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-1.0
N;N;N;N;N
REVEL
Benign
0.091
Sift
Benign
0.27
T;T;T;T;T
Sift4G
Benign
0.81
T;T;T;T;T
Polyphen
0.82, 1.0
.;P;.;D;.
Vest4
0.51
MutPred
0.27
.;Gain of glycosylation at N816 (P = 0.0029);.;Gain of glycosylation at N816 (P = 0.0029);.;
MVP
0.75
MPC
0.36
ClinPred
0.18
T
GERP RS
4.3
Varity_R
0.10
gMVP
0.23

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: rs397514743; hg19: chr1-3329208; COSMIC: COSV54578596; API