rs370046582

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_022114.4(PRDM16):c.2576C>T(p.Ser859Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000761 in 1,484,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S859S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

PRDM16
NM_022114.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 7.42

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

left ventricular noncompaction 8
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
left ventricular noncompaction
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

PRDM16 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1430775).

BP6

Variant 1-3412773-C-T is Benign according to our data. Variant chr1-3412773-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 229164.

BS2

High AC in GnomAd4 at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM16	NM_022114.4 link	c.2576C>T	p.Ser859Leu	missense_variant	Exon 9 of 17	ENST00000270722.10	NP_071397.3	Q9HAZ2-1
PRDM16	NM_199454.3 link	c.2576C>T	p.Ser859Leu	missense_variant	Exon 9 of 17		NP_955533.2	Q9HAZ2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM16	ENST00000270722.10 link	c.2576C>T	p.Ser859Leu	missense_variant	Exon 9 of 17	1	NM_022114.4	ENSP00000270722.5		Q9HAZ2-1

Frequencies

GnomAD3 genomes

AF:

0.000407

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000956

GnomAD2 exomes

AF:

0.0000891

AC:

AN:

101012

AF XY:

0.0000751

show subpopulations

Gnomad AFR exome

AF:

0.000469

Gnomad AMR exome

AF:

0.000244

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000853

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1332100

Hom.:

Cov.:

AF XY:

0.0000400

AC XY:

AN XY:

650578

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

28308

American (AMR)

AF:

0.000188

AC:

AN:

26658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20530

East Asian (EAS)

AF:

0.00

AC:

AN:

34674

South Asian (SAS)

AF:

0.00

AC:

AN:

68150

European-Finnish (FIN)

AF:

0.0000222

AC:

AN:

44964

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5312

European-Non Finnish (NFE)

AF:

0.00000381

AC:

AN:

1048614

Other (OTH)

AF:

0.000128

AC:

AN:

54890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000407

AC:

AN:

152370

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.00139

AC:

AN:

41592

American (AMR)

AF:

0.000131

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000476

ESP6500AA

AF:

0.00134

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000531

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 10, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ser859Leu variant in PRDM16 has not been previously reported in individual s with cardiomyopathy, but has been identified in 0.1% (5/3715) of African Ameri can chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS/; dbSNP rs370046582). Computational prediction tools and conservation an alysis suggest that the p.Ser859Leu variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Ser859Leu variant is uncertain. -

Left ventricular noncompaction 8

Uncertain:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 859 of the PRDM16 protein (p.Ser859Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with sudden unexplained death (PMID: 26350513). ClinVar contains an entry for this variant (Variation ID: 229164). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Benign:1

Jan 15, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26350513) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

T;.;.;T;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.14

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

.;L;.;L;.

PhyloP100

7.4

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.6

N;N;N;N;N

REVEL

Benign

0.22

Sift

Benign

0.14

T;T;T;T;T

Sift4G

Benign

0.22

T;T;T;T;T

Polyphen

0.97, 1.0

.;D;.;D;.

Vest4

0.95

MVP

0.57

MPC

0.35

ClinPred

0.21

GERP RS

4.3

Varity_R

0.16

gMVP

0.69

Mutation Taster

=0/100

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over