1-3186480-C-T

Variant names:

• chr1-3186480-C-T
• rs369010644
• NM_022114.4:c.387+6C>T

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.387+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000743 in 1,480,554 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (1 hom.)
• Consequence: PRDM16 NM_022114.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002610
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.182
• Publications: 0 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=-0.83).
• BP6: Variant 1-3186480-C-T is Benign according to our data. Variant chr1-3186480-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 580 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.387+6C>T		splice_region intron	N/A	NP_071397.3
	PRDM16	NM_199454.3		c.387+6C>T		splice_region 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.387+6C>T		splice_region intron	N/A	ENSP00000270722.5	Q9HAZ2-1
	PRDM16	ENST00000378391.6	TSL:1	c.387+6C>T		splice_region intron	N/A	ENSP00000367643.2	Q9HAZ2-2
	PRDM16	ENST00000511072.5	TSL:5	c.387+6C>T		splice_region intron	N/A	ENSP00000426975.1	D6RDW0

Frequencies

GnomAD3 genomes AF: 0.00383 AC: 583 AN: 152098 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00123 AC: 200 AN: 161992 AF XY: 0.00101

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.000634

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000526

Gnomad OTH exome AF: 0.000532

GnomAD4 exome AF: 0.000391 AC: 520 AN: 1328338 Hom.: 1 Cov.: 23 AF XY: 0.000366 AC XY: 239 AN XY: 653694

African (AFR) AF: 0.0146 AC: 430 AN: 29532

American (AMR) AF: 0.000772 AC: 23 AN: 29786

Ashkenazi Jewish (ASJ) AF: 0.0000498 AC: 1 AN: 20094

East Asian (EAS) AF: 0.00 AC: 0 AN: 38478

South Asian (SAS) AF: 0.0000564 AC: 4 AN: 70878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48016

Middle Eastern (MID) AF: 0.00152 AC: 8 AN: 5256

European-Non Finnish (NFE) AF: 0.0000136 AC: 14 AN: 1031124

Other (OTH) AF: 0.000725 AC: 40 AN: 55174

GnomAD4 genome AF: 0.00381 AC: 580 AN: 152216 Hom.: 7 Cov.: 33 AF XY: 0.00363 AC XY: 270 AN XY: 74396

African (AFR) AF: 0.0133 AC: 554 AN: 41540

American (AMR) AF: 0.000654 AC: 10 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68008

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00216 Hom.: 1

Bravo AF: 0.00457

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	1	Left ventricular noncompaction 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.2
DANN	Benign	0.50
PhyloP100		0.18
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0
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: rs369010644; hg19: chr1-3103044;