rs870124

Positions:

• chr1-3411794-T-C
• chr1-3411794-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022114.4(PRDM16):​c.1597T>C​(p.Ser533Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.855 in 1,611,306 control chromosomes in the GnomAD database, including 590,885 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S533L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.89 (60967 hom., cov: 30)
  • Exomes 𝑓: 0.85 (529918 hom.)
• Consequence: PRDM16 NM_022114.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.03

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.779954E-7).
• BP6: Variant 1-3411794-T-C is Benign according to our data. Variant chr1-3411794-T-C is described in ClinVar as [Benign]. Clinvar id is 227026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-3411794-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM16	NM_022114.4	c.1597T>C	p.Ser533Pro	missense_variant	9/17	ENST00000270722.10
PRDM16	NM_199454.3	c.1597T>C	p.Ser533Pro	missense_variant	9/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM16	ENST00000270722.10	c.1597T>C	p.Ser533Pro	missense_variant	9/17	1	NM_022114.4	P1

Frequencies

GnomAD3 genomes AF: 0.893 AC: 135624 AN: 151882 Hom.: 60900 Cov.: 30

Gnomad AFR AF: 0.970

Gnomad AMI AF: 0.775

Gnomad AMR AF: 0.891

Gnomad ASJ AF: 0.846

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.954

Gnomad FIN AF: 0.916

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.834

Gnomad OTH AF: 0.900

GnomAD3 exomes AF: 0.890 AC: 219507 AN: 246742 Hom.: 97999 AF XY: 0.888 AC XY: 119089 AN XY: 134044

Gnomad AFR exome AF: 0.973

Gnomad AMR exome AF: 0.923

Gnomad ASJ exome AF: 0.853

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.950

Gnomad FIN exome AF: 0.913

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.869

GnomAD4 exome AF: 0.851 AC: 1241375 AN: 1459306 Hom.: 529918 Cov.: 68 AF XY: 0.853 AC XY: 619472 AN XY: 726020

Gnomad4 AFR exome AF: 0.975

Gnomad4 AMR exome AF: 0.919

Gnomad4 ASJ exome AF: 0.851

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.946

Gnomad4 FIN exome AF: 0.913

Gnomad4 NFE exome AF: 0.828

Gnomad4 OTH exome AF: 0.860

GnomAD4 genome AF: 0.893 AC: 135751 AN: 152000 Hom.: 60967 Cov.: 30 AF XY: 0.900 AC XY: 66865 AN XY: 74292

Gnomad4 AFR AF: 0.970

Gnomad4 AMR AF: 0.892

Gnomad4 ASJ AF: 0.846

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.953

Gnomad4 FIN AF: 0.916

Gnomad4 NFE AF: 0.834

Gnomad4 OTH AF: 0.901

Alfa AF: 0.848 Hom.: 73649

Bravo AF: 0.892

TwinsUK AF: 0.838 AC: 3107

ALSPAC AF: 0.841 AC: 3240

ESP6500AA AF: 0.967 AC: 3759

ESP6500EA AF: 0.836 AC: 6902

ExAC AF: 0.890 AC: 107324

Asia WGS AF: 0.978 AC: 3401 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ser533Pro in exon 9 of PRDM16: This variant is not expected to have clinical sig nificance because it has been identified in 16.4% (1358/8260) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs870124). -
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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -

Left ventricular noncompaction 8 Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	14
DANN	Benign	0.66
DEOGEN2	Benign	0.0039	T;.;.;T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.43	T;T;T;T;T
MetaRNN	Benign	5.8e-7	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.91	P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	1.3	N;N;N;N;N
REVEL	Benign	0.089
Sift	Benign	0.65	T;T;T;T;T
Sift4G	Benign	0.45	T;T;T;T;T
Polyphen		0.0	.;B;.;B;.
Vest4		0.035
MPC		0.44
ClinPred		0.0027	T
GERP RS		5.3
Varity_R		0.096
gMVP		0.30

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

Other links and lift over

dbSNP: rs870124; hg19: chr1-3328358; COSMIC: COSV54612185;