chr1-107057165-T-A

Position:

• chr1-107057165-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018137.3(PRMT6):​c.450T>A​(p.Asp150Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PRMT6 NM_018137.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.244

Genes affected

PRMT6 (HGNC:18241): (protein arginine methyltransferase 6) The protein encoded by this gene belongs to the arginine N-methyltransferase family, which catalyze the sequential transfer of methyl group from S-adenosyl-L-methionine to the side chain nitrogens of arginine residues within proteins, to form methylated arginine derivatives and S-adenosyl-L-homocysteine. This protein can catalyze both, the formation of omega-N monomethylarginine and asymmetrical dimethylarginine, with a strong preference for the latter. It specifically mediates the asymmetric dimethylation of Arg2 of histone H3, and the methylated form represents a specific tag for epigenetic transcriptional repression. This protein also forms a complex with, and methylates DNA polymerase beta, resulting in stimulation of polymerase activity by enhancing DNA binding and processivity. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRMT6	NM_018137.3	c.450T>A	p.Asp150Glu	missense_variant	1/1	ENST00000370078.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRMT6	ENST00000370078.2	c.450T>A	p.Asp150Glu	missense_variant	1/1		NM_018137.3	P1
PRMT6	ENST00000650338.1	c.264T>A	p.Asp88Glu	missense_variant, NMD_transcript_variant	1/3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457180 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2022

The c.450T>A (p.D150E) alteration is located in exon 1 (coding exon 1) of the PRMT6 gene. This alteration results from a T to A substitution at nucleotide position 450, causing the aspartic acid (D) at amino acid position 150 to be replaced by a glutamic acid (E). 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	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	19
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.030	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	0.87	D;D;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.41
Sift	Benign	0.061	T
Sift4G	Uncertain	0.054	T
Polyphen		0.99	D
Vest4		0.41
MutPred		0.89		Gain of disorder (P = 0.1101);
MVP		0.69
MPC		1.6
ClinPred		0.99	D
GERP RS		-6.8
Varity_R		0.68
gMVP		0.86

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: rs1651740412; hg19: chr1-107599787;