11-20395940-C-T

Variant names:

• chr11-20395940-C-T
• rs377244029
• NM_005788.4:c.538C>T

Variant summary

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

The NM_005788.4(PRMT3):​c.538C>T​(p.Arg180Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000858 in 1,609,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R180H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: PRMT3 NM_005788.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.43
• Publications: 3 publications found

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]

ACMG classification

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	c.538C>T	p.Arg180Cys	missense_variant	Exon 6 of 16	ENST00000331079.11	NP_005779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRMT3	ENST00000331079.11	c.538C>T	p.Arg180Cys	missense_variant	Exon 6 of 16	1	NM_005788.4	ENSP00000331879.6

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152038 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000649 AC: 16 AN: 246678 AF XY: 0.000113

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000865 AC: 126 AN: 1457162 Hom.: 0 Cov.: 30 AF XY: 0.0000925 AC XY: 67 AN XY: 724570

African (AFR) AF: 0.00 AC: 0 AN: 33238

American (AMR) AF: 0.00 AC: 0 AN: 43344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25928

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39674

South Asian (SAS) AF: 0.000248 AC: 21 AN: 84716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5740

European-Non Finnish (NFE) AF: 0.0000873 AC: 97 AN: 1110868

Other (OTH) AF: 0.0000498 AC: 3 AN: 60258

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74384

African (AFR) AF: 0.0000482 AC: 2 AN: 41496

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000326 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.538C>T (p.R180C) alteration is located in exon 6 (coding exon 6) of the PRMT3 gene. This alteration results from a C to T substitution at nucleotide position 538, causing the arginine (R) at amino acid position 180 to be replaced by a cysteine (C). 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	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.
PhyloP100		3.4
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.12
Sift	Benign	0.077	T;T
Sift4G	Uncertain	0.054	T;T
Polyphen		0.99	D;D
Vest4		0.49
MVP		0.57
MPC		0.28
ClinPred		0.21	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.35
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.27		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs377244029; hg19: chr11-20417486; COSMIC: COSV58178440; COSMIC: COSV58178440;