rs149333409

Positions:

• chr1-3412487-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_022114.4(PRDM16):​c.2290G>A​(p.Val764Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,613,312 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V764G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (3 hom.)
• Consequence: PRDM16 NM_022114.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 1.91

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007611513).
• BP6: Variant 1-3412487-G-A is Benign according to our data. Variant chr1-3412487-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229162.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=1}. Variant chr1-3412487-G-A is described in Lovd as [Benign]. Variant chr1-3412487-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 178 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM16	NM_022114.4	c.2290G>A	p.Val764Met	missense_variant	9/17	ENST00000270722.10
PRDM16	NM_199454.3	c.2290G>A	p.Val764Met	missense_variant	9/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM16	ENST00000270722.10	c.2290G>A	p.Val764Met	missense_variant	9/17	1	NM_022114.4	P1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152070 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00122 AC: 303 AN: 248526 Hom.: 0 AF XY: 0.00126 AC XY: 170 AN XY: 135056

Gnomad AFR exome AF: 0.000454

Gnomad AMR exome AF: 0.000783

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000654

Gnomad FIN exome AF: 0.000281

Gnomad NFE exome AF: 0.00208

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.00170 AC: 2491 AN: 1461124 Hom.: 3 Cov.: 36 AF XY: 0.00166 AC XY: 1206 AN XY: 726914

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000962

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000904

Gnomad4 FIN exome AF: 0.000285

Gnomad4 NFE exome AF: 0.00202

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152188 Hom.: 2 Cov.: 33 AF XY: 0.00106 AC XY: 79 AN XY: 74410

Gnomad4 AFR AF: 0.000482

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00196

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00177 Hom.: 0

Bravo AF: 0.00116

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00240 AC: 20

ExAC AF: 0.00120 AC: 145

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 13, 2018	The p.Val764Met variant in PRDM16 is classified as benign because it has been id entified in 0.2% (257/126116) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). Additionally, computationa l prediction tools and conservation analysis suggest that the p.Val764Met varian t may not impact the protein. ACMG/AMP Criteria applied: BA1, BP4. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The c.2290G>A (p.V764M) alteration is located in exon 9 (coding exon 9) of the PRDM16 gene. This alteration results from a G to A substitution at nucleotide position 2290, causing the valine (V) at amino acid position 764 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

PRDM16-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2020

This variant is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0084	T;.;.;T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.69	T;T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0076	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.92	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.24	N;N;N;N;N
REVEL	Benign	0.017
Sift	Benign	0.075	T;T;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		0.10, 0.80	.;B;.;P;.
Vest4		0.15
MVP		0.29
MPC		0.38
ClinPred		0.0069	T
GERP RS		1.7
Varity_R		0.037
gMVP		0.18

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: rs149333409; hg19: chr1-3329051;