1-3186110-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022114.4(PRDM16):c.38-15C>T 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 0.00122 in 1,602,442 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (16 hom., cov: 33)
  • Exomes 𝑓: 0.00069 (12 hom.)
• Consequence: PRDM16 NM_022114.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.516

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-3186110-C-T is Benign according to our data. Variant chr1-3186110-C-T is described in ClinVar as [Benign]. Clinvar id is 227038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-3186110-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00621 (946/152280) while in subpopulation AFR AF= 0.0211 (876/41564). AF 95% confidence interval is 0.0199. There are 16 homozygotes in gnomad4. There are 423 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 945 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM16	NM_022114.4	c.38-15C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000270722.10
PRDM16	NM_199454.3	c.38-15C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM16	ENST00000270722.10	c.38-15C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_022114.4	P1

Frequencies

GnomAD3 genomes AF: 0.00621 AC: 945 AN: 152162 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00168 AC: 410 AN: 243582 Hom.: 7 AF XY: 0.00119 AC XY: 159 AN XY: 133518

Gnomad AFR exome AF: 0.0226

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000168

Gnomad SAS exome AF: 0.0000983

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.000670

GnomAD4 exome AF: 0.000693 AC: 1005 AN: 1450162 Hom.: 12 Cov.: 29 AF XY: 0.000623 AC XY: 450 AN XY: 722118

Gnomad4 AFR exome AF: 0.0211

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00621 AC: 946 AN: 152280 Hom.: 16 Cov.: 33 AF XY: 0.00568 AC XY: 423 AN XY: 74456

Gnomad4 AFR AF: 0.0211

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00312 Hom.: 1

Bravo AF: 0.00690

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	38-15C>T in intron 1 of PRDM16: This variant is not expected to have clinical si gnificance because it has been identified in 1.5% (65/4322) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs9662053). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 21, 2022

- -

Left ventricular noncompaction 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.2
Dann	Benign	0.46

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: rs9662053; hg19: chr1-3102674;