rs61745281

Variant names:

• chr1-3405575-C-T
• rs61745281
• NM_022114.4:c.1113C>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.1113C>T​(p.Cys371Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00495 in 1,611,340 control chromosomes in the GnomAD database, including 302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (131 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (171 hom.)
• Consequence: PRDM16 NM_022114.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.146
• 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=-0.51).
• BP6: Variant 1-3405575-C-T is Benign according to our data. Variant chr1-3405575-C-T is described in ClinVar as Benign. ClinVar VariationId is 227022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.146 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0781 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.1113C>T	p.Cys371Cys	synonymous	Exon 8 of 17	NP_071397.3
	PRDM16	NM_199454.3		c.1113C>T	p.Cys371Cys	synonymous	Exon 8 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.1113C>T	p.Cys371Cys	synonymous	Exon 8 of 17	ENSP00000270722.5
	PRDM16	ENST00000378391.6	TSL:1	c.1113C>T	p.Cys371Cys	synonymous	Exon 8 of 17	ENSP00000367643.2
	PRDM16	ENST00000512462.5	TSL:1	n.891C>T		non_coding_transcript_exon	Exon 7 of 16

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3597 AN: 152222 Hom.: 129 Cov.: 33

Gnomad AFR AF: 0.0804

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.00667 AC: 1642 AN: 245998 AF XY: 0.00498

Gnomad AFR exome AF: 0.0833

Gnomad AMR exome AF: 0.00526

Gnomad ASJ exome AF: 0.00313

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000930

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00602

GnomAD4 exome AF: 0.00300 AC: 4378 AN: 1459000 Hom.: 171 Cov.: 31 AF XY: 0.00266 AC XY: 1934 AN XY: 725828

African (AFR) AF: 0.0907 AC: 3020 AN: 33308

American (AMR) AF: 0.00655 AC: 292 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00273 AC: 71 AN: 26038

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39542

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86054

European-Finnish (FIN) AF: 0.0000956 AC: 5 AN: 52280

Middle Eastern (MID) AF: 0.0108 AC: 62 AN: 5758

European-Non Finnish (NFE) AF: 0.000441 AC: 490 AN: 1111140

Other (OTH) AF: 0.00690 AC: 416 AN: 60298

GnomAD4 genome AF: 0.0237 AC: 3604 AN: 152340 Hom.: 131 Cov.: 33 AF XY: 0.0229 AC XY: 1707 AN XY: 74492

African (AFR) AF: 0.0803 AC: 3340 AN: 41574

American (AMR) AF: 0.0106 AC: 163 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000676 AC: 46 AN: 68030

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.00837 Hom.: 13

Bravo AF: 0.0268

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00119

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.51
CADD	Benign	6.4
DANN	Benign	0.89
PhyloP100		-0.15
Mutation Taster		=96/4	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: rs61745281; hg19: chr1-3322139;