rs199853370

Variant names:

• chr1-3425743-C-T
• rs199853370
• NM_022114.4:c.3102C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_022114.4(PRDM16):​c.3102C>T​(p.Asn1034Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,613,524 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (11 hom.)
• Consequence: PRDM16 NM_022114.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.06
• 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):

• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 1-3425743-C-T is Benign according to our data. Variant chr1-3425743-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.06 with no splicing effect.
• BS2: High AC in GnomAd4 at 228 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM16	NM_022114.4	MANE Select	c.3102C>T	p.Asn1034Asn	synonymous	Exon 13 of 17	NP_071397.3
	PRDM16	NM_199454.3		c.3102C>T	p.Asn1034Asn	synonymous	Exon 13 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.3102C>T	p.Asn1034Asn	synonymous	Exon 13 of 17	ENSP00000270722.5
	PRDM16	ENST00000378391.6	TSL:1	c.3102C>T	p.Asn1034Asn	synonymous	Exon 13 of 17	ENSP00000367643.2
	PRDM16	ENST00000512462.5	TSL:1	n.2880C>T		non_coding_transcript_exon	Exon 12 of 16

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 229 AN: 152154 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00181 AC: 451 AN: 248886 AF XY: 0.00203

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00627

Gnomad NFE exome AF: 0.00176

Gnomad OTH exome AF: 0.00331

GnomAD4 exome AF: 0.00213 AC: 3117 AN: 1461252 Hom.: 11 Cov.: 32 AF XY: 0.00215 AC XY: 1566 AN XY: 726978

African (AFR) AF: 0.000299 AC: 10 AN: 33476

American (AMR) AF: 0.00119 AC: 53 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00168 AC: 145 AN: 86252

European-Finnish (FIN) AF: 0.00661 AC: 350 AN: 52970

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5766

European-Non Finnish (NFE) AF: 0.00214 AC: 2383 AN: 1111892

Other (OTH) AF: 0.00268 AC: 162 AN: 60376

GnomAD4 genome AF: 0.00150 AC: 228 AN: 152272 Hom.: 1 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74442

African (AFR) AF: 0.000409 AC: 17 AN: 41556

American (AMR) AF: 0.00150 AC: 23 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.00443 AC: 47 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00184 AC: 125 AN: 68022

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00151 Hom.: 0

Bravo AF: 0.00159

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00284

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	-	2	Left ventricular noncompaction 8 (2)
-	-	1	PRDM16-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	3.4
DANN	Benign	0.81
PhyloP100		-1.1
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: rs199853370; hg19: chr1-3342307; COSMIC: COSV54587101;