Genetic Variant NM_005788.4:c.731G>A (chr11-20402944-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_005788.4(PRMT3):c.731G>A(p.Arg244Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000755 in 1,456,640 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 0.0000076 ( 1 hom. )

Consequence

PRMT3
NM_005788.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.56

Publications

0 publications found

Variant links:

Genes affected

PRMT3 (HGNC:30163): (protein arginine methyltransferase 3) This gene belongs to the protein arginine methyltransferase (PRMT) family. The encoded enzyme catalyzes the methylation of guanidino nitrogens of arginyl residues of proteins. The enzyme acts on 40S ribosomal protein S2 (rpS2), which is its major in-vivo substrate, and is involved in the proper maturation of the 80S ribosome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

PRMT3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRMT3	NM_005788.4 link	c.731G>A	p.Arg244Gln	missense_variant	Exon 8 of 16	ENST00000331079.11	NP_005779.1	O60678-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRMT3	ENST00000331079.11 link	c.731G>A	p.Arg244Gln	missense_variant	Exon 8 of 16	1	NM_005788.4	ENSP00000331879.6	O60678-1
PRMT3	ENST00000330796.9 link	n.*454G>A		non_coding_transcript_exon_variant	Exon 7 of 15	1		ENSP00000329586.5	E9PLF6
PRMT3	ENST00000330796.9 link	n.*454G>A		3_prime_UTR_variant	Exon 7 of 15	1		ENSP00000329586.5	E9PLF6
PRMT3	ENST00000437750.2 link	c.545G>A	p.Arg182Gln	missense_variant	Exon 6 of 14	2		ENSP00000397766.2	O60678-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251272

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000755

AC:

AN:

1456640

Hom.:

Cov.:

AF XY:

0.00000966

AC XY:

AN XY:

725008

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33314

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39606

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86132

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000451

AC:

AN:

1107460

Other (OTH)

AF:

0.0000332

AC:

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 10, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.731G>A (p.R244Q) alteration is located in exon 8 (coding exon 8) of the PRMT3 gene. This alteration results from a G to A substitution at nucleotide position 731, causing the arginine (R) at amino acid position 244 to be replaced by a glutamine (Q). 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

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

D;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.033

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

9.6

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.032

D;D

Polyphen

0.98

D;D

Vest4

0.76

MutPred

0.59

Loss of phosphorylation at S242 (P = 0.0929);.;

MVP

0.73

MPC

0.35

ClinPred

0.99

GERP RS

5.5

Varity_R

0.72

gMVP

0.77

Mutation Taster

=42/58

disease causing

(source)

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

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NM_005788.4:c.731G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over