Genetic Variant PRMT3:p.Phe254Leu (chr11-20402973-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_005788.4(PRMT3):c.760T>C(p.Phe254Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000906 in 1,597,532 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00095 ( 0 hom. )

Consequence

PRMT3
NM_005788.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.64

Publications

6 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRMT3	NM_005788.4 link	c.760T>C	p.Phe254Leu	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.760T>C	p.Phe254Leu	missense_variant	Exon 8 of 16	1	NM_005788.4	ENSP00000331879.6	O60678-1
PRMT3	ENST00000330796.9 link	n.*483T>C		non_coding_transcript_exon_variant	Exon 7 of 15	1		ENSP00000329586.5	E9PLF6
PRMT3	ENST00000330796.9 link	n.*483T>C		3_prime_UTR_variant	Exon 7 of 15	1		ENSP00000329586.5	E9PLF6
PRMT3	ENST00000437750.2 link	c.574T>C	p.Phe192Leu	missense_variant	Exon 6 of 14	2		ENSP00000397766.2	O60678-2

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000852

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000394

AC:

AN:

251206

AF XY:

0.000361

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000417

Gnomad NFE exome

AF:

0.000739

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000952

AC:

1376

AN:

1445176

Hom.:

Cov.:

AF XY:

0.000908

AC XY:

654

AN XY:

719944

show subpopulations

African (AFR)

AF:

0.000151

AC:

AN:

33048

American (AMR)

AF:

0.00

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26028

East Asian (EAS)

AF:

0.00

AC:

AN:

39532

South Asian (SAS)

AF:

0.00

AC:

AN:

85890

European-Finnish (FIN)

AF:

0.000375

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00121

AC:

1328

AN:

1097040

Other (OTH)

AF:

0.000368

AC:

AN:

59850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

127

191

254

318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000473

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41586

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000853

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000814

Hom.:

Bravo

AF:

0.000404

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000436

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.760T>C (p.F254L) alteration is located in exon 8 (coding exon 8) of the PRMT3 gene. This alteration results from a T to C substitution at nucleotide position 760, causing the phenylalanine (F) at amino acid position 254 to be replaced by a leucine (L). 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

0.95

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.026

MetaRNN

Uncertain

0.45

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.56

N;.

PhyloP100

7.6

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.8

D;D

REVEL

Uncertain

0.44

Sift

Uncertain

0.022

D;D

Sift4G

Benign

0.12

T;D

Polyphen

0.99

D;D

Vest4

0.81

MutPred

0.63

Loss of methylation at K255 (P = 0.0317);.;

MVP

0.56

MPC

0.45

ClinPred

0.27

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.61

gMVP

0.76

Mutation Taster

=35/65

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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11-20402973-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over