rs201654872

Positions:

• chr1-3430888-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022114.4(PRDM16):​c.3301G>A​(p.Val1101Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,614,114 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00079 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (43 hom.)
• Consequence: PRDM16 NM_022114.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: 2.22

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]

PRDM16 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005124122).
• BP6: Variant 1-3430888-G-A is Benign according to our data. Variant chr1-3430888-G-A is described in ClinVar as [Benign]. Clinvar id is 60727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-3430888-G-A is described in Lovd as [Benign]. Variant chr1-3430888-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000794 (121/152342) while in subpopulation SAS AF= 0.0224 (108/4820). AF 95% confidence interval is 0.019. There are 3 homozygotes in gnomad4. There are 91 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 121 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM16	NM_022114.4	c.3301G>A	p.Val1101Met	missense_variant	15/17	ENST00000270722.10	NP_071397.3
PRDM16	NM_199454.3	c.3301G>A	p.Val1101Met	missense_variant	15/17		NP_955533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM16	ENST00000270722.10	c.3301G>A	p.Val1101Met	missense_variant	15/17	1	NM_022114.4	ENSP00000270722.5

Frequencies

GnomAD3 genomes AF: 0.000788 AC: 120 AN: 152224 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00317 AC: 785 AN: 247326 Hom.: 13 AF XY: 0.00426 AC XY: 572 AN XY: 134392

Gnomad AFR exome AF: 0.000193

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0250

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00157 AC: 2288 AN: 1461772 Hom.: 43 Cov.: 32 AF XY: 0.00222 AC XY: 1612 AN XY: 727178

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0242

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.000794 AC: 121 AN: 152342 Hom.: 3 Cov.: 33 AF XY: 0.00122 AC XY: 91 AN XY: 74494

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0224

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000323 Hom.: 0

Bravo AF: 0.000230

ExAC AF: 0.00353 AC: 428

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 29, 2015	p.Val1101Met in exon 15 of PRDM16: This variant is not expected to have clinical significance because it has been identified in 2.6% (422/16468) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs201654872). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2018	This variant is associated with the following publications: (PMID: 27896284, 27535533, 24387995, 23768516) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PRDM16: BP4, BS1, BS2 -

Left ventricular noncompaction 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Val1101Met variant in PRDM16 has been identified in 2 individuals with dilated cardiomyopathy (PMID: 23768516), and has been identified in >2% of South Asian chromosomes and 7 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal dominant dilated cardiomyopathy. -

Cardiomyopathy, dilated, 1LL Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Jul 11, 2013

- -

PRDM16-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2024

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	17
DANN	Benign	0.82
DEOGEN2	Benign	0.010	T;.;.;T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.48	T;T;T;T;T
MetaRNN	Benign	0.0051	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	.;N;.;N;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.40	N;N;N;N;N
REVEL	Benign	0.033
Sift	Benign	0.21	T;T;T;T;T
Sift4G	Benign	0.17	T;T;T;T;T
Polyphen		0.099, 0.81	.;B;.;P;.
Vest4		0.18
MVP		0.16
MPC		0.071
ClinPred		0.0078	T
GERP RS		1.7
Varity_R		0.025
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: rs201654872; hg19: chr1-3347452;