rs2483221

chr1-3405533-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_022114.4(PRDM16):c.1071C>T(p.Arg357=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,603,902 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (24 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (28 hom.)
• Consequence: PRDM16 NM_022114.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.140

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 1-3405533-C-T is Benign according to our data. Variant chr1-3405533-C-T is described in ClinVar as [Benign]. Clinvar id is 221025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-3405533-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00861 (1311/152302) while in subpopulation AFR AF= 0.0289 (1201/41570). AF 95% confidence interval is 0.0275. There are 24 homozygotes in gnomad4. There are 625 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1311 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM16	NM_022114.4	c.1071C>T	p.Arg357=	synonymous_variant	8/17	ENST00000270722.10
PRDM16	NM_199454.3	c.1071C>T	p.Arg357=	synonymous_variant	8/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM16	ENST00000270722.10	c.1071C>T	p.Arg357=	synonymous_variant	8/17	1	NM_022114.4	P1

Frequencies

GnomAD3 genomes AF: 0.00861 AC: 1311 AN: 152184 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.0290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00235 AC: 557 AN: 237500 Hom.: 11 AF XY: 0.00185 AC XY: 240 AN XY: 129708

Gnomad AFR exome AF: 0.0288

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.000421

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000681

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.00139

GnomAD4 exome AF: 0.00101 AC: 1468 AN: 1451600 Hom.: 28 Cov.: 31 AF XY: 0.000900 AC XY: 650 AN XY: 721886

Gnomad4 AFR exome AF: 0.0274

Gnomad4 AMR exome AF: 0.00245

Gnomad4 ASJ exome AF: 0.000623

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000517

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.000216

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.00861 AC: 1311 AN: 152302 Hom.: 24 Cov.: 33 AF XY: 0.00839 AC XY: 625 AN XY: 74464

Gnomad4 AFR AF: 0.0289

Gnomad4 AMR AF: 0.00457

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00273 Hom.: 2

Bravo AF: 0.00939

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Arg357Arg in exon 8 of PRDM16: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 2.7% (120/4400) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs2483221). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

PRDM16-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2019

This variant is classified as 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	13
Dann	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2483221; hg19: chr1-3322097;