rs61745281

Positions:

• chr1-3405575-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.1113C>T​(p.Cys371=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00495 in 1,611,340 control chromosomes in the GnomAD database, including 302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (131 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (171 hom.)
• Consequence: PRDM16 NM_022114.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.146

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=-0.51).
• BP6: Variant 1-3405575-C-T is Benign according to our data. Variant chr1-3405575-C-T is described in ClinVar as [Benign]. Clinvar id is 227022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-3405575-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.146 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM16	NM_022114.4	c.1113C>T	p.Cys371=	synonymous_variant	8/17	ENST00000270722.10
PRDM16	NM_199454.3	c.1113C>T	p.Cys371=	synonymous_variant	8/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM16	ENST00000270722.10	c.1113C>T	p.Cys371=	synonymous_variant	8/17	1	NM_022114.4	P1

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3597 AN: 152222 Hom.: 129 Cov.: 33

Gnomad AFR AF: 0.0804

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.00667 AC: 1642 AN: 245998 Hom.: 64 AF XY: 0.00498 AC XY: 667 AN XY: 133938

Gnomad AFR exome AF: 0.0833

Gnomad AMR exome AF: 0.00526

Gnomad ASJ exome AF: 0.00313

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000658

Gnomad FIN exome AF: 0.0000930

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00602

GnomAD4 exome AF: 0.00300 AC: 4378 AN: 1459000 Hom.: 171 Cov.: 31 AF XY: 0.00266 AC XY: 1934 AN XY: 725828

Gnomad4 AFR exome AF: 0.0907

Gnomad4 AMR exome AF: 0.00655

Gnomad4 ASJ exome AF: 0.00273

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.0000956

Gnomad4 NFE exome AF: 0.000441

Gnomad4 OTH exome AF: 0.00690

GnomAD4 genome AF: 0.0237 AC: 3604 AN: 152340 Hom.: 131 Cov.: 33 AF XY: 0.0229 AC XY: 1707 AN XY: 74492

Gnomad4 AFR AF: 0.0803

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.00741 Hom.: 7

Bravo AF: 0.0268

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00119

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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 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	Cys371Cys 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 8.3% (363/4398) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs61745281). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Apr 17, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 28, 2023

- -

Left ventricular noncompaction 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.4
DANN	Benign	0.89

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: rs61745281; hg19: chr1-3322139;