chr1-3069264-G-A

Position:

• chr1-3069264-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000270722.10(PRDM16):​c.5G>A​(p.Arg2Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRDM16 ENST00000270722.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.64

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]

LOC124903827 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3748707).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM16	NM_022114.4	c.5G>A	p.Arg2Gln	missense_variant	1/17	ENST00000270722.10	NP_071397.3
LOC124903827	XM_047436614.1	c.1651-293C>T		intron_variant			XP_047292570.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM16	ENST00000270722.10	c.5G>A	p.Arg2Gln	missense_variant	1/17	1	NM_022114.4	ENSP00000270722	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1419072 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 705294

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Left ventricular noncompaction 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2020

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. 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 C0"). This variant has not been reported in the literature in individuals with PRDM16-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 2 of the PRDM16 protein (p.Arg2Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T;.;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	.;L;.;L
MutationTaster	Benign	0.53	N;N;N;N;N;N;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.14	N;N;N;N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.036, 0.021	.;B;.;B
Vest4		0.37
MutPred		0.22		Loss of methylation at R2 (P = 0.0052);Loss of methylation at R2 (P = 0.0052);Loss of methylation at R2 (P = 0.0052);Loss of methylation at R2 (P = 0.0052);
MVP		0.35
MPC		1.2
ClinPred		0.62	D
GERP RS		1.8
Varity_R		0.77
gMVP		0.12

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-2985828;