rs371654192

Positions:

• chr1-3412665-G-A
• chr1-3412665-G-C
• chr1-3412665-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM5 BP4_Strong BP6_Very_Strong BS2

The NM_022114.4(PRDM16):​c.2468G>A​(p.Arg823His) variant causes a missense change. The variant allele was found at a frequency of 0.000251 in 1,524,294 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R823C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: PRDM16 NM_022114.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.30

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-3412665-G-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.00794363).
• BP6: Variant 1-3412665-G-A is Benign according to our data. Variant chr1-3412665-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 510913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-3412665-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM16	NM_022114.4	c.2468G>A	p.Arg823His	missense_variant	9/17	ENST00000270722.10
PRDM16	NM_199454.3	c.2468G>A	p.Arg823His	missense_variant	9/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM16	ENST00000270722.10	c.2468G>A	p.Arg823His	missense_variant	9/17	1	NM_022114.4	P1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00461

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000471 AC: 63 AN: 133652 Hom.: 0 AF XY: 0.000572 AC XY: 42 AN XY: 73440

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000479

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00125

Gnomad FIN exome AF: 0.00332

Gnomad NFE exome AF: 0.0000712

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000234 AC: 321 AN: 1371968 Hom.: 2 Cov.: 36 AF XY: 0.000274 AC XY: 185 AN XY: 674654

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000308

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000278

Gnomad4 SAS exome AF: 0.00113

Gnomad4 FIN exome AF: 0.00377

Gnomad4 NFE exome AF: 0.0000524

Gnomad4 OTH exome AF: 0.000177

GnomAD4 genome AF: 0.000400 AC: 61 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.000591 AC XY: 44 AN XY: 74484

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00461

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000219 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.000490 AC: 55

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 19, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Left ventricular noncompaction 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;.;.;T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
MetaRNN	Benign	0.0079	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	.;M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.2	N;N;N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D
Polyphen		1.0, 1.0	.;D;.;D;.
Vest4		0.65
MVP		0.57
MPC		1.2
ClinPred		0.11	T
GERP RS		4.3
Varity_R		0.20
gMVP		0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs371654192; hg19: chr1-3329229;