rs2493292

chr1-3412095-C-T

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.1898C>T(p.Pro633Leu) variant causes a missense change. The variant allele was found at a frequency of 0.135 in 1,586,060 control chromosomes in the GnomAD database, including 15,641 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1614 hom., cov: 33)
  • Exomes 𝑓: 0.13 (14027 hom.)
• Consequence: PRDM16 NM_022114.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.65

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=0.0017106235).
• BP6: Variant 1-3412095-C-T is Benign according to our data. Variant chr1-3412095-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-3412095-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM16	NM_022114.4	c.1898C>T	p.Pro633Leu	missense_variant	9/17	ENST00000270722.10
PRDM16	NM_199454.3	c.1898C>T	p.Pro633Leu	missense_variant	9/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM16	ENST00000270722.10	c.1898C>T	p.Pro633Leu	missense_variant	9/17	1	NM_022114.4	P1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21321 AN: 151990 Hom.: 1612 Cov.: 33

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.00931

Gnomad SAS AF: 0.0720

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.158

GnomAD3 exomes AF: 0.123 AC: 28161 AN: 228982 Hom.: 2098 AF XY: 0.125 AC XY: 15454 AN XY: 123872

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.0802

Gnomad ASJ exome AF: 0.223

Gnomad EAS exome AF: 0.0108

Gnomad SAS exome AF: 0.0762

Gnomad FIN exome AF: 0.0988

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.135 AC: 193548 AN: 1433952 Hom.: 14027 Cov.: 37 AF XY: 0.134 AC XY: 95216 AN XY: 709876

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.0849

Gnomad4 ASJ exome AF: 0.215

Gnomad4 EAS exome AF: 0.00691

Gnomad4 SAS exome AF: 0.0774

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.144

Gnomad4 OTH exome AF: 0.139

GnomAD4 genome AF: 0.140 AC: 21323 AN: 152108 Hom.: 1614 Cov.: 33 AF XY: 0.136 AC XY: 10139 AN XY: 74358

Gnomad4 AFR AF: 0.163

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.214

Gnomad4 EAS AF: 0.00933

Gnomad4 SAS AF: 0.0715

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.148

Gnomad4 OTH AF: 0.158

Alfa AF: 0.151 Hom.: 4449

Bravo AF: 0.143

TwinsUK AF: 0.139 AC: 516

ALSPAC AF: 0.145 AC: 558

ESP6500AA AF: 0.154 AC: 659

ESP6500EA AF: 0.152 AC: 1283

ExAC AF: 0.126 AC: 15289

Asia WGS AF: 0.0560 AC: 195 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Pro633Leu in exon 9 of PRDM16: This variant is not expected to have clinical sig nificance because it has been identified in 15.4% (659/4286) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs2493292). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Left ventricular noncompaction 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0055	T;.;.;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.037
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
MetaRNN	Benign	0.0017	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	0.097	P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.23	N;N;N;N;N
REVEL	Benign	0.074
Sift	Uncertain	0.023	D;D;D;D;D
Sift4G	Benign	0.33	T;T;T;T;T
Polyphen		0.066, 0.039	.;B;.;B;.
Vest4		0.076
MPC		0.37
ClinPred		0.016	T
GERP RS		4.2
Varity_R		0.047
gMVP		0.11

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: rs2493292; hg19: chr1-3328659; COSMIC: COSV54601867;