1-3417934-G-C

Variant names:

• chr1-3417934-G-C
• rs572092688
• NM_022114.4:c.2798G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_022114.4(PRDM16):​c.2798G>C​(p.Arg933Pro) variant causes a missense change involving the alteration of a conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R933W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRDM16 NM_022114.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.44
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• left ventricular noncompaction 8

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022114.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM16	NM_022114.4	MANE Select	c.2798G>C	p.Arg933Pro	missense	Exon 11 of 17	NP_071397.3
	PRDM16	NM_199454.3		c.2798G>C	p.Arg933Pro	missense	Exon 11 of 17	NP_955533.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM16	ENST00000270722.10	TSL:1 MANE Select	c.2798G>C	p.Arg933Pro	missense	Exon 11 of 17	ENSP00000270722.5
	PRDM16	ENST00000378391.6	TSL:1	c.2798G>C	p.Arg933Pro	missense	Exon 11 of 17	ENSP00000367643.2
	PRDM16	ENST00000512462.5	TSL:1	n.2576G>C		non_coding_transcript_exon	Exon 10 of 16

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 143864 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000151 AC: 2 AN: 1324160 Hom.: 0 Cov.: 35 AF XY: 0.00000152 AC XY: 1 AN XY: 659130

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29616

American (AMR) AF: 0.00 AC: 0 AN: 39548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21692

East Asian (EAS) AF: 0.00 AC: 0 AN: 31104

South Asian (SAS) AF: 0.0000240 AC: 2 AN: 83360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5156

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1021812

Other (OTH) AF: 0.00 AC: 0 AN: 51770

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 143958 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 70036

African (AFR) AF: 0.00 AC: 0 AN: 39316

American (AMR) AF: 0.00 AC: 0 AN: 14452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.00 AC: 0 AN: 4462

South Asian (SAS) AF: 0.00 AC: 0 AN: 4072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65832

Other (OTH) AF: 0.00 AC: 0 AN: 2016

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.051	T
Polyphen		0.16	B
Vest4		0.86
MutPred		0.25		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.50
MPC		1.4
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.76
gMVP		0.87
Mutation Taster		=32/68	disease causing

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

Other links and lift over

dbSNP: rs572092688; hg19: chr1-3334498;