1-3363689-G-A

Variant names:

• chr1-3363689-G-A
• rs6658356
• NM_022114.4:c.439-21463G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022114.4(PRDM16):​c.439-21463G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 152,074 control chromosomes in the GnomAD database, including 1,516 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.12 (1516 hom., cov: 32)
• Consequence: PRDM16 NM_022114.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.436
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.243 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.439-21463G>A		intron	N/A	NP_071397.3
	PRDM16	NM_199454.3		c.439-21463G>A		intron	N/A	NP_955533.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM16	ENST00000270722.10	TSL:1 MANE Select	c.439-21463G>A		intron	N/A	ENSP00000270722.5
	PRDM16	ENST00000378391.6	TSL:1	c.439-21463G>A		intron	N/A	ENSP00000367643.2
	PRDM16	ENST00000512462.5	TSL:1	n.217-21463G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17727 AN: 151956 Hom.: 1510 Cov.: 32

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.0621

Gnomad ASJ AF: 0.0576

Gnomad EAS AF: 0.0315

Gnomad SAS AF: 0.0952

Gnomad FIN AF: 0.0849

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0671

Gnomad OTH AF: 0.0920

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.117 AC: 17762 AN: 152074 Hom.: 1516 Cov.: 32 AF XY: 0.114 AC XY: 8501 AN XY: 74340

African (AFR) AF: 0.247 AC: 10224 AN: 41434

American (AMR) AF: 0.0618 AC: 944 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0576 AC: 200 AN: 3472

East Asian (EAS) AF: 0.0318 AC: 164 AN: 5158

South Asian (SAS) AF: 0.0946 AC: 455 AN: 4808

European-Finnish (FIN) AF: 0.0849 AC: 901 AN: 10608

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0671 AC: 4562 AN: 67998

Other (OTH) AF: 0.0948 AC: 200 AN: 2110

Alfa AF: 0.0795 Hom.: 2178

Bravo AF: 0.121

Asia WGS AF: 0.0980 AC: 342 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.64
DANN	Benign	0.33
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: rs6658356; hg19: chr1-3280253;