1-3425762-G-C

Variant names:

• chr1-3425762-G-C
• rs200643126
• NM_022114.4:c.3109+12G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_022114.4(PRDM16):​c.3109+12G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,612,952 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (4 hom.)
• Consequence: PRDM16 NM_022114.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.82
• Publications: 1 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-3425762-G-C is Benign according to our data. Variant chr1-3425762-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 290 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM16	NM_022114.4	MANE Select	c.3109+12G>C		intron	N/A	NP_071397.3
	PRDM16	NM_199454.3		c.3109+12G>C		intron	N/A	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.3109+12G>C		intron	N/A	ENSP00000270722.5	Q9HAZ2-1
	PRDM16	ENST00000378391.6	TSL:1	c.3109+12G>C		intron	N/A	ENSP00000367643.2	Q9HAZ2-2
	PRDM16	ENST00000512462.5	TSL:1	n.2887+12G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 290 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00294

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00179 AC: 442 AN: 247522 AF XY: 0.00181

Gnomad AFR exome AF: 0.000456

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00532

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00196 AC: 2862 AN: 1460688 Hom.: 4 Cov.: 32 AF XY: 0.00200 AC XY: 1452 AN XY: 726674

African (AFR) AF: 0.000269 AC: 9 AN: 33476

American (AMR) AF: 0.00110 AC: 49 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26086

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86218

European-Finnish (FIN) AF: 0.00560 AC: 295 AN: 52688

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00217 AC: 2411 AN: 1111710

Other (OTH) AF: 0.00147 AC: 89 AN: 60360

GnomAD4 genome AF: 0.00190 AC: 290 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.00200 AC XY: 149 AN XY: 74444

African (AFR) AF: 0.000193 AC: 8 AN: 41556

American (AMR) AF: 0.00150 AC: 23 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00518 AC: 55 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00294 AC: 200 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00201 Hom.: 0

Bravo AF: 0.00159

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.37
DANN	Benign	0.28
PhyloP100		2.8
Mutation Taster		=100/0	polymorphism

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: rs200643126; hg19: chr1-3342326;