1-3186110-C-T

Variant names:

• chr1-3186110-C-T
• rs9662053
• NM_022114.4:c.38-15C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022114.4(PRDM16):​c.38-15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,602,442 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (16 hom., cov: 33)
  • Exomes 𝑓: 0.00069 (12 hom.)
• Consequence: PRDM16 NM_022114.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.516
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-3186110-C-T is Benign according to our data. Variant chr1-3186110-C-T is described in ClinVar as Benign. ClinVar VariationId is 227038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00621 (946/152280) while in subpopulation AFR AF = 0.0211 (876/41564). AF 95% confidence interval is 0.0199. There are 16 homozygotes in GnomAd4. There are 423 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 946 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.38-15C>T		intron	N/A	NP_071397.3
	PRDM16	NM_199454.3		c.38-15C>T		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.38-15C>T		intron	N/A	ENSP00000270722.5	Q9HAZ2-1
	PRDM16	ENST00000378391.6	TSL:1	c.38-15C>T		intron	N/A	ENSP00000367643.2	Q9HAZ2-2
	PRDM16	ENST00000511072.5	TSL:5	c.38-15C>T		intron	N/A	ENSP00000426975.1	D6RDW0

Frequencies

GnomAD3 genomes AF: 0.00621 AC: 945 AN: 152162 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00168 AC: 410 AN: 243582 AF XY: 0.00119

Gnomad AFR exome AF: 0.0226

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.000670

GnomAD4 exome AF: 0.000693 AC: 1005 AN: 1450162 Hom.: 12 Cov.: 29 AF XY: 0.000623 AC XY: 450 AN XY: 722118

African (AFR) AF: 0.0211 AC: 703 AN: 33270

American (AMR) AF: 0.00152 AC: 68 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39640

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52128

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5740

European-Non Finnish (NFE) AF: 0.000119 AC: 131 AN: 1102586

Other (OTH) AF: 0.00118 AC: 71 AN: 60034

GnomAD4 genome AF: 0.00621 AC: 946 AN: 152280 Hom.: 16 Cov.: 33 AF XY: 0.00568 AC XY: 423 AN XY: 74456

African (AFR) AF: 0.0211 AC: 876 AN: 41564

American (AMR) AF: 0.00307 AC: 47 AN: 15300

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68002

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

Alfa AF: 0.00299 Hom.: 1

Bravo AF: 0.00690

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.46
PhyloP100		-0.52
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: rs9662053; hg19: chr1-3102674;