rs529401311

Positions:

• chr1-3411942-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_022114.4(PRDM16):​c.1745G>A​(p.Arg582His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000961 in 1,613,580 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: PRDM16 NM_022114.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 1.79

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021018684).
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM16	NM_022114.4	c.1745G>A	p.Arg582His	missense_variant	9/17	ENST00000270722.10	NP_071397.3
PRDM16	NM_199454.3	c.1745G>A	p.Arg582His	missense_variant	9/17		NP_955533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM16	ENST00000270722.10	c.1745G>A	p.Arg582His	missense_variant	9/17	1	NM_022114.4	ENSP00000270722	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152128 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000145 AC: 36 AN: 248780 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135124

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.000883

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000532

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000103 AC: 150 AN: 1461452 Hom.: 1 Cov.: 37 AF XY: 0.000125 AC XY: 91 AN XY: 727026

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000951

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152128 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74302

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000186 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 03, 2017	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 25, 2018	p.Arg582His (c.1745G>A) in Exon 9 of the PRDM16 gene (NM_022114.3) Chromosome location: 1:3328506 G / A Based on the information reviewed below, including the lack of case data, and the fact that it is 10x more common in individuals like our patient who have Asian ancestry, we classify this as a Variant of Uncertain Significance, Probably Benign. The PRDM16 gene currently has no well-established disease association; however, there is preliminary evidence supporting a correlation with autosomal dominant left ventricular noncompaction (LVNC) (MedGen UID: 349005) and dilated cardiomyopathy (DCM) (OMIM: 615373). This variant has not previously been reported in the literature in association with disease, according to the Invitae report. This is a conservative amino acid change, resulting in the replacement of a positively-charged Arginine with a positively-charged Histidine. Arginine at this location is poorly conserved across ~100 vertebrate species for which we have data. The adjacent residues are also poorly conserved. The Histidine variant is found as the default amino acid in at least 5 mammalian species, suggesting that this missense change does not adversely affect protein function. There are no Likely Pathogenic or Pathogenic variants currently listed in ClinVar within 10 amino acids to either side. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). These predictions have not been confirmed by published functional studies This variant was reported in 40 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 27 individuals with South Asian ancestry (for the highest allele frequency: 0.09%), 7 non-Finnish Europeans, 3 East Asians, 1 Latino, and 2 “Other”. Overall MAF 0.01%. There is also one individual with a different variant at this location: p.Arg582Cys. There is good sequencing coverage at this site. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -

Left ventricular noncompaction 8 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 474412). This variant has not been reported in the literature in individuals affected with PRDM16-related conditions. This variant is present in population databases (rs529401311, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 582 of the PRDM16 protein (p.Arg582His). -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The c.1745G>A (p.R582H) alteration is located in exon 9 (coding exon 9) of the PRDM16 gene. This alteration results from a G to A substitution at nucleotide position 1745, causing the arginine (R) at amino acid position 582 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0084	T;.;.;T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.72	T;T;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.021	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	.;L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.33	N;N;N;N;N
REVEL	Benign	0.022
Sift	Benign	0.098	T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T
Polyphen		0.0040, 0.0010	.;B;.;B;.
Vest4		0.11
MutPred		0.14		.;Gain of glycosylation at K578 (P = 0.173);.;Gain of glycosylation at K578 (P = 0.173);.;
MVP		0.21
MPC		0.44
ClinPred		0.031	T
GERP RS		2.2
Varity_R		0.020
gMVP		0.25

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: rs529401311; hg19: chr1-3328506; COSMIC: COSV54604519;