1-3385266-A-G

Position:

chr1-3385266-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000270722.10(PRDM16):c.553A>G(p.Met185Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000861 in 1,613,648 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00052 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

PRDM16
ENST00000270722.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.54

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016035497).

BP6

Variant 1-3385266-A-G is Benign according to our data. Variant chr1-3385266-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235271.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr1-3385266-A-G is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM16	NM_022114.4 linkuse as main transcript	c.553A>G	p.Met185Val	missense_variant	4/17	ENST00000270722.10	NP_071397.3
PRDM16	NM_199454.3 linkuse as main transcript	c.553A>G	p.Met185Val	missense_variant	4/17		NP_955533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM16	ENST00000270722.10 linkuse as main transcript	c.553A>G	p.Met185Val	missense_variant	4/17	1	NM_022114.4	ENSP00000270722	P1	Q9HAZ2-1

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000140

AC:

AN:

249172

Hom.:

AF XY:

0.0000887

AC XY:

AN XY:

135318

show subpopulations

Gnomad AFR exome

AF:

0.00175

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000411

AC:

AN:

1461354

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726956

show subpopulations

Gnomad4 AFR exome

AF:

0.00116

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000519

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00178

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000265

Hom.:

Bravo

AF:

0.000601

ESP6500AA

AF:

0.000703

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 11, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 2020	- -

PRDM16-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2024

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.012

T;.;.;T;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.66

T;T;T;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.016

T;T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.0

.;N;.;N;.

MutationTaster

Benign

1.0

D;N;N;N;N;N;N;N

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.44

N;N;N;N;.

REVEL

Benign

0.13

Sift

Benign

0.50

T;T;T;T;.

Sift4G

Benign

0.52

T;T;T;T;T

Polyphen

0.0010, 0.0

.;B;.;B;.

Vest4

0.15

MVP

0.54

MPC

0.36

ClinPred

0.043

GERP RS

3.3

Varity_R

0.18

gMVP

0.31

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over