1-3412699-C-T

Variant names:

• chr1-3412699-C-T
• rs115226069
• NM_022114.4:c.2502C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022114.4(PRDM16):​c.2502C>T​(p.Gly834Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.024 in 1,493,972 control chromosomes in the GnomAD database, including 767 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (224 hom., cov: 33)
  • Exomes 𝑓: 0.022 (543 hom.)
• Consequence: PRDM16 NM_022114.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.436
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-3412699-C-T is Benign according to our data. Variant chr1-3412699-C-T is described in ClinVar as Benign. ClinVar VariationId is 227029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.436 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0998 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM16	NM_022114.4	MANE Select	c.2502C>T	p.Gly834Gly	synonymous	Exon 9 of 17	NP_071397.3
	PRDM16	NM_199454.3		c.2502C>T	p.Gly834Gly	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.2502C>T	p.Gly834Gly	synonymous	Exon 9 of 17	ENSP00000270722.5
	PRDM16	ENST00000378391.6	TSL:1	c.2502C>T	p.Gly834Gly	synonymous	Exon 9 of 17	ENSP00000367643.2
	PRDM16	ENST00000512462.5	TSL:1	n.2280C>T		non_coding_transcript_exon	Exon 8 of 16

Frequencies

GnomAD3 genomes AF: 0.0426 AC: 6480 AN: 152152 Hom.: 223 Cov.: 33

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00985

Gnomad SAS AF: 0.0648

Gnomad FIN AF: 0.0152

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0193

Gnomad OTH AF: 0.0307

GnomAD2 exomes AF: 0.0270 AC: 2805 AN: 103700 AF XY: 0.0278

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.00895

Gnomad ASJ exome AF: 0.00796

Gnomad EAS exome AF: 0.0125

Gnomad FIN exome AF: 0.0156

Gnomad NFE exome AF: 0.0196

Gnomad OTH exome AF: 0.0182

GnomAD4 exome AF: 0.0219 AC: 29392 AN: 1341702 Hom.: 543 Cov.: 36 AF XY: 0.0225 AC XY: 14751 AN XY: 656660

African (AFR) AF: 0.105 AC: 3063 AN: 29304

American (AMR) AF: 0.0101 AC: 272 AN: 26824

Ashkenazi Jewish (ASJ) AF: 0.00590 AC: 128 AN: 21704

East Asian (EAS) AF: 0.00866 AC: 303 AN: 34980

South Asian (SAS) AF: 0.0531 AC: 3768 AN: 70994

European-Finnish (FIN) AF: 0.0158 AC: 687 AN: 43556

Middle Eastern (MID) AF: 0.00870 AC: 47 AN: 5404

European-Non Finnish (NFE) AF: 0.0188 AC: 19810 AN: 1053626

Other (OTH) AF: 0.0238 AC: 1314 AN: 55310

GnomAD4 genome AF: 0.0426 AC: 6481 AN: 152270 Hom.: 224 Cov.: 33 AF XY: 0.0417 AC XY: 3107 AN XY: 74460

African (AFR) AF: 0.102 AC: 4253 AN: 41554

American (AMR) AF: 0.0199 AC: 305 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.00987 AC: 51 AN: 5166

South Asian (SAS) AF: 0.0649 AC: 313 AN: 4824

European-Finnish (FIN) AF: 0.0152 AC: 161 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0193 AC: 1310 AN: 68004

Other (OTH) AF: 0.0303 AC: 64 AN: 2110

Alfa AF: 0.0292 Hom.: 36

Bravo AF: 0.0447

Asia WGS AF: 0.0360 AC: 127 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Oct 06, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 10, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Gly834Gly in exon 9 of PRDM16: This variant is not expected to have clinical s ignificance because it has been identified in 9.1% (303/3320) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs115226069).

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Left ventricular noncompaction 8 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.63
PhyloP100		0.44
Mutation Taster		=100/0	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: rs115226069; hg19: chr1-3329263; COSMIC: COSV54597776;