ENST00000687743.2:n.39_41delGCC

Variant names:

• chr1-3069056-AGGC-A
• rs534904951
• ENST00000687743.2:n.39_41delGCC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The ENST00000687743.2(PRDM16-DT):​n.39_41delGCC 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 0.0107 in 492,934 control chromosomes in the GnomAD database, including 81 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (74 hom., cov: 29)
  • Exomes 𝑓: 0.0076 (7 hom.)
• Consequence: PRDM16-DT ENST00000687743.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.28
• Publications: 0 publications found

Genes affected

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

LOC124903827 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-3069056-AGGC-A is Benign according to our data. Variant chr1-3069056-AGGC-A is described in ClinVar as [Benign]. Clinvar id is 1276988.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM16	NM_022114.4	c.-203_-201delGGC		upstream_gene_variant		ENST00000270722.10	NP_071397.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM16	ENST00000270722.10	c.-203_-201delGGC		upstream_gene_variant		1	NM_022114.4	ENSP00000270722.5

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2668 AN: 149110 Hom.: 74 Cov.: 29

Gnomad AFR AF: 0.0598

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.00174

Gnomad EAS AF: 0.000201

Gnomad SAS AF: 0.000215

Gnomad FIN AF: 0.000291

Gnomad MID AF: 0.0166

Gnomad NFE AF: 0.000859

Gnomad OTH AF: 0.0116

GnomAD4 exome AF: 0.00760 AC: 2613 AN: 343716 Hom.: 7 AF XY: 0.00725 AC XY: 1378 AN XY: 190028

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0545 AC: 350 AN: 6426

American (AMR) AF: 0.0124 AC: 158 AN: 12754

Ashkenazi Jewish (ASJ) AF: 0.00549 AC: 74 AN: 13468

East Asian (EAS) AF: 0.00433 AC: 81 AN: 18696

South Asian (SAS) AF: 0.00640 AC: 270 AN: 42202

European-Finnish (FIN) AF: 0.00582 AC: 171 AN: 29380

Middle Eastern (MID) AF: 0.00545 AC: 9 AN: 1650

European-Non Finnish (NFE) AF: 0.00641 AC: 1284 AN: 200452

Other (OTH) AF: 0.0116 AC: 216 AN: 18688

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0179 AC: 2670 AN: 149218 Hom.: 74 Cov.: 29 AF XY: 0.0176 AC XY: 1286 AN XY: 72888

African (AFR) AF: 0.0598 AC: 2385 AN: 39912

American (AMR) AF: 0.0124 AC: 188 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.00174 AC: 6 AN: 3452

East Asian (EAS) AF: 0.000201 AC: 1 AN: 4970

South Asian (SAS) AF: 0.000215 AC: 1 AN: 4650

European-Finnish (FIN) AF: 0.000291 AC: 3 AN: 10316

Middle Eastern (MID) AF: 0.0108 AC: 3 AN: 278

European-Non Finnish (NFE) AF: 0.000860 AC: 58 AN: 67474

Other (OTH) AF: 0.0115 AC: 24 AN: 2086

Alfa AF: 0.0000643 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 25, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3

Splicing

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

Other links and lift over

dbSNP: rs534904951; hg19: chr1-2985620;