rs870124

Variant names:

• chr1-3411794-T-C
• rs870124
• NM_022114.4:c.1597T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-3411794-T-C
• chr1-3411794-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022114.4(PRDM16):​c.1597T>C​(p.Ser533Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.855 in 1,611,306 control chromosomes in the GnomAD database, including 590,885 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S533A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.89 (60967 hom., cov: 30)
  • Exomes 𝑓: 0.85 (529918 hom.)
• Consequence: PRDM16 NM_022114.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.03
• Publications: 34 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.779954E-7).
• BP6: Variant 1-3411794-T-C is Benign according to our data. Variant chr1-3411794-T-C is described in ClinVar as Benign. ClinVar VariationId is 227026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM16	NM_022114.4	MANE Select	c.1597T>C	p.Ser533Pro	missense	Exon 9 of 17	NP_071397.3
	PRDM16	NM_199454.3		c.1597T>C	p.Ser533Pro	missense	Exon 9 of 17	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.1597T>C	p.Ser533Pro	missense	Exon 9 of 17	ENSP00000270722.5	Q9HAZ2-1
	PRDM16	ENST00000378391.6	TSL:1	c.1597T>C	p.Ser533Pro	missense	Exon 9 of 17	ENSP00000367643.2	Q9HAZ2-2
	PRDM16	ENST00000512462.5	TSL:1	n.1375T>C		non_coding_transcript_exon	Exon 8 of 16

Frequencies

GnomAD3 genomes AF: 0.893 AC: 135624 AN: 151882 Hom.: 60900 Cov.: 30

Gnomad AFR AF: 0.970

Gnomad AMI AF: 0.775

Gnomad AMR AF: 0.891

Gnomad ASJ AF: 0.846

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.954

Gnomad FIN AF: 0.916

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.834

Gnomad OTH AF: 0.900

GnomAD2 exomes AF: 0.890 AC: 219507 AN: 246742 AF XY: 0.888

Gnomad AFR exome AF: 0.973

Gnomad AMR exome AF: 0.923

Gnomad ASJ exome AF: 0.853

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.913

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.869

GnomAD4 exome AF: 0.851 AC: 1241375 AN: 1459306 Hom.: 529918 Cov.: 68 AF XY: 0.853 AC XY: 619472 AN XY: 726020

African (AFR) AF: 0.975 AC: 32631 AN: 33476

American (AMR) AF: 0.919 AC: 41075 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.851 AC: 22202 AN: 26100

East Asian (EAS) AF: 1.00 AC: 39678 AN: 39692

South Asian (SAS) AF: 0.946 AC: 81604 AN: 86220

European-Finnish (FIN) AF: 0.913 AC: 46930 AN: 51402

Middle Eastern (MID) AF: 0.904 AC: 5211 AN: 5762

European-Non Finnish (NFE) AF: 0.828 AC: 920144 AN: 1111604

Other (OTH) AF: 0.860 AC: 51900 AN: 60358

GnomAD4 genome AF: 0.893 AC: 135751 AN: 152000 Hom.: 60967 Cov.: 30 AF XY: 0.900 AC XY: 66865 AN XY: 74292

African (AFR) AF: 0.970 AC: 40261 AN: 41486

American (AMR) AF: 0.892 AC: 13641 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.846 AC: 2933 AN: 3468

East Asian (EAS) AF: 0.999 AC: 5117 AN: 5124

South Asian (SAS) AF: 0.953 AC: 4582 AN: 4808

European-Finnish (FIN) AF: 0.916 AC: 9698 AN: 10588

Middle Eastern (MID) AF: 0.891 AC: 262 AN: 294

European-Non Finnish (NFE) AF: 0.834 AC: 56653 AN: 67916

Other (OTH) AF: 0.901 AC: 1897 AN: 2106

Alfa AF: 0.854 Hom.: 114150

Bravo AF: 0.892

TwinsUK AF: 0.838 AC: 3107

ALSPAC AF: 0.841 AC: 3240

ESP6500AA AF: 0.967 AC: 3759

ESP6500EA AF: 0.836 AC: 6902

ExAC AF: 0.890 AC: 107324

Asia WGS AF: 0.978 AC: 3401 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Left ventricular noncompaction 8 (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	14
DANN	Benign	0.66
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	5.8e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.7	N
PhyloP100		2.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.089
Sift	Benign	0.65	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.035
MPC		0.44
ClinPred		0.0027	T
GERP RS		5.3
Varity_R		0.096
gMVP		0.30
Mutation Taster		=100/0	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: rs870124; hg19: chr1-3328358; COSMIC: COSV54612185;