rs199968728

chr1-3186229-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_022114.4(PRDM16):c.142G>A(p.Val48Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0005 in 1,612,586 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00056 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (7 hom.)
• Consequence: PRDM16 NM_022114.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.24

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007950783).
• BP6: Variant 1-3186229-G-A is Benign according to our data. Variant chr1-3186229-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-3186229-G-A is described in Lovd as [Benign]. Variant chr1-3186229-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 85 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM16	NM_022114.4	c.142G>A	p.Val48Met	missense_variant	2/17	ENST00000270722.10
PRDM16	NM_199454.3	c.142G>A	p.Val48Met	missense_variant	2/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM16	ENST00000270722.10	c.142G>A	p.Val48Met	missense_variant	2/17	1	NM_022114.4	P1

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152176 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.000789 AC: 195 AN: 247058 Hom.: 0 AF XY: 0.000758 AC XY: 102 AN XY: 134642

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000899

Gnomad ASJ exome AF: 0.00663

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000449

Gnomad OTH exome AF: 0.000998

GnomAD4 exome AF: 0.000494 AC: 722 AN: 1460292 Hom.: 7 Cov.: 31 AF XY: 0.000531 AC XY: 386 AN XY: 726430

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000962

Gnomad4 ASJ exome AF: 0.00639

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00129

Gnomad4 FIN exome AF: 0.0000383

Gnomad4 NFE exome AF: 0.000267

Gnomad4 OTH exome AF: 0.000779

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152294 Hom.: 1 Cov.: 33 AF XY: 0.000604 AC XY: 45 AN XY: 74460

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.000949 Hom.: 0

Bravo AF: 0.000593

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000591 AC: 5

ExAC AF: 0.000752 AC: 91

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 04, 2016	p.Val48Met in exon 2 of PRDM16: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, >20 species have a methionine (Met) at this position despite high nearby am ino acid conservation. In addition, computational prediction tools do not sugges t a high likelihood of impact to the protein. It has been identified in 0.13% (2 1/16314) of South Asian and 0.10% (62/64490) European chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199968728). -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

PRDM16-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2019

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). -

Left ventricular noncompaction 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	10
Dann	Benign	0.11
DEOGEN2	Benign	0.0071	T;.;.;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.0080	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.94	N;N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.23	N;N;N;N
REVEL	Benign	0.066
Sift	Benign	0.86	T;T;T;T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.028, 0.0060	.;B;.;B
Vest4		0.22
MVP		0.28
MPC		0.35
ClinPred		0.0041	T
GERP RS		2.3
Varity_R		0.026
gMVP		0.13

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: rs199968728; hg19: chr1-3102793;