1-3412444-G-C

Position:

• chr1-3412444-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022114.4(PRDM16):​c.2247G>C​(p.Leu749Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,438 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L749L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRDM16 NM_022114.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.52

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26176578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM16	NM_022114.4	c.2247G>C	p.Leu749Phe	missense_variant	9/17	ENST00000270722.10	NP_071397.3
PRDM16	NM_199454.3	c.2247G>C	p.Leu749Phe	missense_variant	9/17		NP_955533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM16	ENST00000270722.10	c.2247G>C	p.Leu749Phe	missense_variant	9/17	1	NM_022114.4	ENSP00000270722.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460438 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 726454

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2024

The c.2247G>C (p.L749F) alteration is located in exon 9 (coding exon 9) of the PRDM16 gene. This alteration results from a G to C substitution at nucleotide position 2247, causing the leucine (L) at amino acid position 749 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Left ventricular noncompaction 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 18, 2022

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 749 of the PRDM16 protein (p.Leu749Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PRDM16-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T;.;.;T;.
Eigen	Benign	0.015
Eigen_PC	Benign	-0.035
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	.;M;.;M;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.5	N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.037	D;D;D;D;D
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		0.90, 0.99	.;P;.;D;.
Vest4		0.48
MutPred		0.53		.;Loss of ubiquitination at K752 (P = 0.0738);.;Loss of ubiquitination at K752 (P = 0.0738);.;
MVP		0.27
MPC		1.1
ClinPred		0.72	D
GERP RS		2.6
Varity_R		0.089
gMVP		0.28

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: rs1553176942; hg19: chr1-3329008;