rs139129844

Variant names:

• chr1-3411409-G-A
• rs139129844
• NM_022114.4:c.1212G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_022114.4(PRDM16):​c.1212G>A​(p.Thr404Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00575 in 1,613,132 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (26 hom.)
• Consequence: PRDM16 NM_022114.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0380
• Publications: 2 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 1-3411409-G-A is Benign according to our data. Variant chr1-3411409-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.038 with no splicing effect.
• BS2: High AC in GnomAd4 at 648 AD gene.

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.1212G>A	p.Thr404Thr	synonymous	Exon 9 of 17	NP_071397.3
	PRDM16	NM_199454.3		c.1212G>A	p.Thr404Thr	synonymous	Exon 9 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.1212G>A	p.Thr404Thr	synonymous	Exon 9 of 17	ENSP00000270722.5
	PRDM16	ENST00000378391.6	TSL:1	c.1212G>A	p.Thr404Thr	synonymous	Exon 9 of 17	ENSP00000367643.2
	PRDM16	ENST00000512462.5	TSL:1	n.990G>A		non_coding_transcript_exon	Exon 8 of 16

Frequencies

GnomAD3 genomes AF: 0.00426 AC: 648 AN: 152200 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00698

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00369 AC: 919 AN: 248934 AF XY: 0.00361

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00283

Gnomad NFE exome AF: 0.00620

Gnomad OTH exome AF: 0.00397

GnomAD4 exome AF: 0.00591 AC: 8630 AN: 1460814 Hom.: 26 Cov.: 32 AF XY: 0.00575 AC XY: 4180 AN XY: 726502

African (AFR) AF: 0.00108 AC: 36 AN: 33458

American (AMR) AF: 0.00219 AC: 98 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00436 AC: 114 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39672

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86238

European-Finnish (FIN) AF: 0.00382 AC: 204 AN: 53402

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00708 AC: 7865 AN: 1111122

Other (OTH) AF: 0.00512 AC: 309 AN: 60344

GnomAD4 genome AF: 0.00425 AC: 648 AN: 152318 Hom.: 2 Cov.: 33 AF XY: 0.00403 AC XY: 300 AN XY: 74484

African (AFR) AF: 0.00154 AC: 64 AN: 41564

American (AMR) AF: 0.00353 AC: 54 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00698 AC: 475 AN: 68030

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00593 Hom.: 3

Bravo AF: 0.00419

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00594

EpiControl AF: 0.00634

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Left ventricular noncompaction 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	8.7
DANN	Benign	0.71
PhyloP100		-0.038
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs139129844; hg19: chr1-3327973;