chr1-3430993-G-C

Variant names:

• chr1-3430993-G-C
• rs775245244
• NM_022114.4:c.3406G>C

Variant summary

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

The NM_022114.4(PRDM16):​c.3406G>C​(p.Gly1136Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PRDM16 NM_022114.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.60

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3197317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM16	NM_022114.4	c.3406G>C	p.Gly1136Arg	missense_variant	Exon 15 of 17	ENST00000270722.10	NP_071397.3
PRDM16	NM_199454.3	c.3406G>C	p.Gly1136Arg	missense_variant	Exon 15 of 17		NP_955533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM16	ENST00000270722.10	c.3406G>C	p.Gly1136Arg	missense_variant	Exon 15 of 17	1	NM_022114.4	ENSP00000270722.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448660 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719512

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;.;.;T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.32	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	.;M;.;M;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.5	D;D;D;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Benign	0.37	T;T;T;T;T
Polyphen		0.99, 0.95	.;D;.;P;.
Vest4		0.48
MutPred		0.091		.;Loss of glycosylation at S1133 (P = 0.0802);Loss of glycosylation at S1133 (P = 0.0802);Loss of glycosylation at S1133 (P = 0.0802);.;
MVP		0.31
MPC		0.12
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.36
gMVP		0.25

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: rs775245244; hg19: chr1-3347557;