1-3402907-G-T

Position:

• chr1-3402907-G-T

Variant summary

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

The NM_022114.4(PRDM16):​c.793G>T​(p.Ala265Ser) 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. 13/21 in silico tools predict 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. A265V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRDM16 NM_022114.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.47

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 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=0.08428064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM16	NM_022114.4	c.793G>T	p.Ala265Ser	missense_variant	6/17	ENST00000270722.10
PRDM16	NM_199454.3	c.793G>T	p.Ala265Ser	missense_variant	6/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM16	ENST00000270722.10	c.793G>T	p.Ala265Ser	missense_variant	6/17	1	NM_022114.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Invitae

Dec 01, 2023

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 265 of the PRDM16 protein (p.Ala265Ser). 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. ClinVar contains an entry for this variant (Variation ID: 541382). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	0.072
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	17
DANN	Benign	0.68
DEOGEN2	Benign	0.0032	T;.;.;T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.71	T;T;T;T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.084	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.69	.;N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.11	N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.85	T;T;T;T;T
Sift4G	Benign	0.78	T;T;T;T;T
Polyphen		0.0010	.;B;.;B;.
Vest4		0.096
MutPred		0.26		.;Gain of phosphorylation at A265 (P = 0.0336);.;Gain of phosphorylation at A265 (P = 0.0336);.;
MVP		0.23
MPC		0.32
ClinPred		0.21	T
GERP RS		3.3
Varity_R		0.053
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

LitVar

Other links and lift over

dbSNP: rs1553174330; hg19: chr1-3319471;