1-3412286-G-T

Position:

• chr1-3412286-G-T

Variant summary

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

The NM_022114.4(PRDM16):​c.2089G>T​(p.Ala697Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,210 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A697T) has been classified as Uncertain significance.

• 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: 9.80

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 2 ACMG points.

• 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.2089G>T	p.Ala697Ser	missense_variant	9/17	ENST00000270722.10	NP_071397.3
PRDM16	NM_199454.3	c.2089G>T	p.Ala697Ser	missense_variant	9/17		NP_955533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM16	ENST00000270722.10	c.2089G>T	p.Ala697Ser	missense_variant	9/17	1	NM_022114.4	ENSP00000270722.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248940 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135180

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461210 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 726908

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 22, 2015

The p.Ala697Ser variant in PRDM16 has not been previously reported in individual s with cardiomyopathy, but has been identified in 2/66264 European chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Compu tational prediction tools and conservation analysis do not provide strong suppor t for or against an impact to the protein. In summary, the clinical significance of the p.Ala697Ser variant is uncertain. -

Left ventricular noncompaction 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 16, 2017

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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with PRDM16-related disease. ClinVar contains an entry for this variant (Variation ID: 229161). This variant is present in population databases (rs779334537, ExAC 0.003%). This sequence change replaces alanine with serine at codon 697 of the PRDM16 protein (p.Ala697Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T;.;.;T;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.54	D;D;D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.5	.;M;.;M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Benign	0.27	T;T;T;T;T
Polyphen		1.0, 0.99	.;D;.;D;.
Vest4		0.78
MutPred		0.40		.;Gain of disorder (P = 0.046);.;Gain of disorder (P = 0.046);.;
MVP		0.63
MPC		1.1
ClinPred		0.93	D
GERP RS		4.7
Varity_R		0.32
gMVP		0.17

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: rs779334537; hg19: chr1-3328850;