rs199614349

chr1-3186288-G-Achr1-3186288-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_022114.4(PRDM16):c.201G>A(p.Pro67=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,611,576 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (14 hom.)
• Consequence: PRDM16 NM_022114.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.823

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 1-3186288-G-A is Benign according to our data. Variant chr1-3186288-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-3186288-G-A is described in Lovd as [Benign]. Variant chr1-3186288-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.823 with no splicing effect.
• BS2: High AC in GnomAd at 246 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM16	NM_022114.4	c.201G>A	p.Pro67=	synonymous_variant	2/17	ENST00000270722.10
PRDM16	NM_199454.3	c.201G>A	p.Pro67=	synonymous_variant	2/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM16	ENST00000270722.10	c.201G>A	p.Pro67=	synonymous_variant	2/17	1	NM_022114.4	P1

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 246 AN: 152168 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00225 AC: 552 AN: 245588 Hom.: 4 AF XY: 0.00244 AC XY: 326 AN XY: 133878

Gnomad AFR exome AF: 0.000391

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.0203

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.000233

Gnomad NFE exome AF: 0.00210

Gnomad OTH exome AF: 0.00351

GnomAD4 exome AF: 0.00173 AC: 2521 AN: 1459290 Hom.: 14 Cov.: 31 AF XY: 0.00179 AC XY: 1302 AN XY: 725834

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.0193

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00132

Gnomad4 FIN exome AF: 0.000250

Gnomad4 NFE exome AF: 0.00140

Gnomad4 OTH exome AF: 0.00307

GnomAD4 genome AF: 0.00162 AC: 246 AN: 152286 Hom.: 1 Cov.: 33 AF XY: 0.00169 AC XY: 126 AN XY: 74470

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00184

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00290 Hom.: 1

Bravo AF: 0.00159

EpiCase AF: 0.00278

EpiControl AF: 0.00314

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2017	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	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	p.Pro67Pro in exon 2 of PRDM16: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.3% (212/64514) o f European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs199614349). -
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, Academic Medical Center	-	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

-

- -

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	-0.59
Cadd	Benign	8.9
Dann	Benign	0.70

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: rs199614349; hg19: chr1-3102852;