rs368409902

chr1-3186111-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_022114.4(PRDM16):c.38-14G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000433 in 1,605,030 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).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (0 hom.)
• Consequence: PRDM16 NM_022114.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -2.50

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 1-3186111-G-A is Benign according to our data. Variant chr1-3186111-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229168.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}. Variant chr1-3186111-G-A is described in Lovd as [Benign]. Variant chr1-3186111-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 84 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM16	NM_022114.4	c.38-14G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000270722.10
PRDM16	NM_199454.3	c.38-14G>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM16	ENST00000270722.10	c.38-14G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_022114.4	P1

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000463 AC: 113 AN: 243840 Hom.: 0 AF XY: 0.000449 AC XY: 60 AN XY: 133626

Gnomad AFR exome AF: 0.000134

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00282

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000672

Gnomad OTH exome AF: 0.000502

GnomAD4 exome AF: 0.000421 AC: 611 AN: 1452710 Hom.: 0 Cov.: 29 AF XY: 0.000445 AC XY: 322 AN XY: 723234

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000326

Gnomad4 NFE exome AF: 0.000456

Gnomad4 OTH exome AF: 0.000499

GnomAD4 genome AF: 0.000551 AC: 84 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.000524 AC XY: 39 AN XY: 74482

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000468

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 14, 2015	Variant classified as Uncertain Significance - Favor Benign. The c.38-14G>A vari ant in PRDM16 has not been previously reported in individuals with cardiomyopath y, but has been identified in 0.1% (59/62964) of European chromosomes by the Exo me Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs3684099 02). This variant is located in the 3' splice region. Computational tools do not suggest an impact to splicing. However, this information is not predictive enou gh to rule out pathogenicity. In summary, while the clinical significance of the c.38-14G>A variant is uncertain, its frequency suggests that it is more likely to be benign. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

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Left ventricular noncompaction 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	0.0010
Dann	Benign	0.58

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

Other links and lift over

dbSNP: rs368409902; hg19: chr1-3102675;