Genetic Variant PRDM16-DT:n.36_41dupGCCGCC (chr1-3069056-A-AGGCGGC) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The ENST00000687743.2(PRDM16-DT):n.36_41dupGCCGCC variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 500,702 control chromosomes in the GnomAD database, including 20 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0072 ( 12 hom., cov: 29)

Exomes 𝑓: 0.0029 ( 8 hom. )

Consequence

PRDM16-DT
ENST00000687743.2 non_coding_transcript_exon

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.569

Publications

0 publications found

Variant links:

Genes affected

PRDM16-DT (HGNC:48664): (PRDM16 divergent transcript)

PRDM16-DT links:

LOC124903827 (HGNC:):

LOC124903827 links:

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00721 (1076/149258) while in subpopulation AFR AF = 0.0201 (804/39934). AF 95% confidence interval is 0.019. There are 12 homozygotes in GnomAd4. There are 510 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM16	NM_022114.4 link	c.-204_-203insGGCGGC		upstream_gene_variant		ENST00000270722.10	NP_071397.3	Q9HAZ2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM16	ENST00000270722.10 link	c.-204_-203insGGCGGC		upstream_gene_variant		1	NM_022114.4	ENSP00000270722.5		Q9HAZ2-1

Frequencies

GnomAD3 genomes

AF:

0.00720

AC:

1074

AN:

149150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0202

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00686

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00966

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00662

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.00727

GnomAD4 exome

AF:

0.00292

AC:

1025

AN:

351444

Hom.:

AF XY:

0.00347

AC XY:

675

AN XY:

194438

show subpopulations

African (AFR)

AF:

0.0138

AC:

AN:

6522

American (AMR)

AF:

0.00332

AC:

AN:

12950

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13728

East Asian (EAS)

AF:

0.00

AC:

AN:

19044

South Asian (SAS)

AF:

0.0117

AC:

506

AN:

43390

European-Finnish (FIN)

AF:

0.0000665

AC:

AN:

30058

Middle Eastern (MID)

AF:

0.00832

AC:

AN:

1682

European-Non Finnish (NFE)

AF:

0.00153

AC:

313

AN:

205058

Other (OTH)

AF:

0.00300

AC:

AN:

19012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.553

Heterozygous variant carriers

135

180

225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00721

AC:

1076

AN:

149258

Hom.:

Cov.:

AF XY:

0.00700

AC XY:

510

AN XY:

72904

show subpopulations

African (AFR)

AF:

0.0201

AC:

804

AN:

39934

American (AMR)

AF:

0.00685

AC:

104

AN:

15174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

4970

South Asian (SAS)

AF:

0.00968

AC:

AN:

4648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10326

Middle Eastern (MID)

AF:

0.00719

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.00156

AC:

105

AN:

67482

Other (OTH)

AF:

0.00767

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

101

151

202

252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000193

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.57

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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1-3069056-AGGCGGCGGCGGCGGC-AGGCGGCGGCGGCGGCGGCGGC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over