1-3417941-AC-ACCC

Position:

• chr1-3417941-AC-ACCC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_022114.4(PRDM16):​c.2809_2810dupCC​(p.Thr938fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRDM16 NM_022114.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.74

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM16	NM_022114.4	c.2809_2810dupCC	p.Thr938fs	frameshift_variant	11/17	ENST00000270722.10	NP_071397.3
PRDM16	NM_199454.3	c.2809_2810dupCC	p.Thr938fs	frameshift_variant	11/17		NP_955533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM16	ENST00000270722.10	c.2809_2810dupCC	p.Thr938fs	frameshift_variant	11/17	1	NM_022114.4	ENSP00000270722.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 02, 2016

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr938Gln fsX34 variant in PRDM16 has not been previously reported in individuals with car diomyopathy or in large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at positio n 938 and leads to a premature termination codon 34 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozy gous deletions including the PRDM16 gene have been reported in individuals with 1p36 deletion syndrome (with cardiac phenotypes including septal defects and LVN C). However, the specific role of the PRDM16 gene is not clear (Arndt 2013, De L eeuw 2014) and small intra-exonic loss of function variants have not yet been we ll studied. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Thr938GlnfsX34 variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657961; hg19: chr1-3334505;