rs12058363

Positions:

• chr1-3396544-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022114.4(PRDM16):​c.627C>T​(p.His209=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00394 in 1,607,358 control chromosomes in the GnomAD database, including 187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (89 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (98 hom.)
• Consequence: PRDM16 NM_022114.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0860

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-3396544-C-T is Benign according to our data. Variant chr1-3396544-C-T is described in ClinVar as [Benign]. Clinvar id is 227042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-3396544-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.086 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM16	NM_022114.4	c.627C>T	p.His209=	synonymous_variant	5/17	ENST00000270722.10	NP_071397.3
PRDM16	NM_199454.3	c.627C>T	p.His209=	synonymous_variant	5/17		NP_955533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM16	ENST00000270722.10	c.627C>T	p.His209=	synonymous_variant	5/17	1	NM_022114.4	ENSP00000270722	P1

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2958 AN: 152146 Hom.: 89 Cov.: 33

Gnomad AFR AF: 0.0656

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00948

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00468 AC: 1112 AN: 237376 Hom.: 27 AF XY: 0.00350 AC XY: 452 AN XY: 129000

Gnomad AFR exome AF: 0.0630

Gnomad AMR exome AF: 0.00346

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000208

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000594

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00232 AC: 3369 AN: 1455094 Hom.: 98 Cov.: 29 AF XY: 0.00204 AC XY: 1475 AN XY: 723316

Gnomad4 AFR exome AF: 0.0658

Gnomad4 AMR exome AF: 0.00440

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000284

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000511

Gnomad4 OTH exome AF: 0.00584

GnomAD4 genome AF: 0.0195 AC: 2968 AN: 152264 Hom.: 89 Cov.: 33 AF XY: 0.0183 AC XY: 1364 AN XY: 74450

Gnomad4 AFR AF: 0.0657

Gnomad4 AMR AF: 0.00947

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000809

Gnomad4 OTH AF: 0.0157

Alfa AF: 0.00868 Hom.: 19

Bravo AF: 0.0220

Asia WGS AF: 0.00375 AC: 14 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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	His209His in exon 5 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 5.6% (235/4164) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs12058363). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Left ventricular noncompaction 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.7
DANN	Benign	0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12058363; hg19: chr1-3313108;