rs2493292

Variant names:

• chr1-3412095-C-T
• rs2493292
• NM_022114.4:c.1898C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022114.4(PRDM16):​c.1898C>T​(p.Pro633Leu) variant causes a missense change. The variant allele was found at a frequency of 0.135 in 1,586,060 control chromosomes in the GnomAD database, including 15,641 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1614 hom., cov: 33)
  • Exomes 𝑓: 0.13 (14027 hom.)
• Consequence: PRDM16 NM_022114.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.65
• Publications: 35 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):

• dilated cardiomyopathy

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• left ventricular noncompaction 8

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017106235).
• BP6: Variant 1-3412095-C-T is Benign according to our data. Variant chr1-3412095-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM16	NM_022114.4	MANE Select	c.1898C>T	p.Pro633Leu	missense	Exon 9 of 17	NP_071397.3
	PRDM16	NM_199454.3		c.1898C>T	p.Pro633Leu	missense	Exon 9 of 17	NP_955533.2	Q9HAZ2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM16	ENST00000270722.10	TSL:1 MANE Select	c.1898C>T	p.Pro633Leu	missense	Exon 9 of 17	ENSP00000270722.5	Q9HAZ2-1
	PRDM16	ENST00000378391.6	TSL:1	c.1898C>T	p.Pro633Leu	missense	Exon 9 of 17	ENSP00000367643.2	Q9HAZ2-2
	PRDM16	ENST00000512462.5	TSL:1	n.1676C>T		non_coding_transcript_exon	Exon 8 of 16

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21321 AN: 151990 Hom.: 1612 Cov.: 33

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.00931

Gnomad SAS AF: 0.0720

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.158

GnomAD2 exomes AF: 0.123 AC: 28161 AN: 228982 AF XY: 0.125

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.0802

Gnomad ASJ exome AF: 0.223

Gnomad EAS exome AF: 0.0108

Gnomad FIN exome AF: 0.0988

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.135 AC: 193548 AN: 1433952 Hom.: 14027 Cov.: 37 AF XY: 0.134 AC XY: 95216 AN XY: 709876

African (AFR) AF: 0.161 AC: 5269 AN: 32678

American (AMR) AF: 0.0849 AC: 3588 AN: 42262

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 5239 AN: 24378

East Asian (EAS) AF: 0.00691 AC: 272 AN: 39356

South Asian (SAS) AF: 0.0774 AC: 6402 AN: 82666

European-Finnish (FIN) AF: 0.106 AC: 5455 AN: 51668

Middle Eastern (MID) AF: 0.244 AC: 1371 AN: 5612

European-Non Finnish (NFE) AF: 0.144 AC: 157760 AN: 1096364

Other (OTH) AF: 0.139 AC: 8192 AN: 58968

GnomAD4 genome AF: 0.140 AC: 21323 AN: 152108 Hom.: 1614 Cov.: 33 AF XY: 0.136 AC XY: 10139 AN XY: 74358

African (AFR) AF: 0.163 AC: 6776 AN: 41498

American (AMR) AF: 0.115 AC: 1763 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 744 AN: 3472

East Asian (EAS) AF: 0.00933 AC: 48 AN: 5142

South Asian (SAS) AF: 0.0715 AC: 344 AN: 4814

European-Finnish (FIN) AF: 0.102 AC: 1087 AN: 10612

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10069 AN: 67954

Other (OTH) AF: 0.158 AC: 334 AN: 2116

Alfa AF: 0.148 Hom.: 7826

Bravo AF: 0.143

TwinsUK AF: 0.139 AC: 516

ALSPAC AF: 0.145 AC: 558

ESP6500AA AF: 0.154 AC: 659

ESP6500EA AF: 0.152 AC: 1283

ExAC AF: 0.126 AC: 15289

Asia WGS AF: 0.0560 AC: 195 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Left ventricular noncompaction 8 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.037
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.074
Sift	Uncertain	0.023	D
Sift4G	Benign	0.33	T
Polyphen		0.066	B
Vest4		0.076
MPC		0.37
ClinPred		0.016	T
GERP RS		4.2
Varity_R		0.047
gMVP		0.11
Mutation Taster		=99/1	polymorphism (auto)

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: rs2493292; hg19: chr1-3328659; COSMIC: COSV54601867;