1-3411385-T-G

Variant names:

• chr1-3411385-T-G
• rs201309284
• NM_022114.4:c.1188T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_022114.4(PRDM16):​c.1188T>G​(p.Cys396Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C396C) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRDM16 NM_022114.4 missense, splice_region
• Scores: Splicing: ADA: 0.0009823
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM16	NM_022114.4	c.1188T>G	p.Cys396Trp	missense_variant, splice_region_variant	Exon 9 of 17	ENST00000270722.10	NP_071397.3
PRDM16	NM_199454.3	c.1188T>G	p.Cys396Trp	missense_variant, splice_region_variant	Exon 9 of 17		NP_955533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM16	ENST00000270722.10	c.1188T>G	p.Cys396Trp	missense_variant, splice_region_variant	Exon 9 of 17	1	NM_022114.4	ENSP00000270722.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;.;.;D;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Pathogenic	4.2	.;H;.;H;.
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-9.3	D;D;D;D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D;D
Polyphen		0.78, 1.0	.;P;.;D;.
Vest4		0.96
MutPred		0.82		.;Gain of MoRF binding (P = 0.0677);.;Gain of MoRF binding (P = 0.0677);.;
MVP		0.95
MPC		1.1
ClinPred		1.0	D
GERP RS		0.096
Varity_R		0.94
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00098
dbscSNV1_RF	Benign	0.024
SpliceAI score (max)		0.12		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: rs201309284; hg19: chr1-3327949;