21-46643598-T-C

Position:

• chr21-46643598-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_206962.4(PRMT2):​c.103T>C​(p.Phe35Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: PRMT2 NM_206962.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14

Genes affected

PRMT2 (HGNC:5186): (protein arginine methyltransferase 2) Enables several functions, including nuclear receptor binding activity; peroxisome proliferator activated receptor binding activity; and protein homodimerization activity. Involved in several processes, including histone methylation; regulation of androgen receptor signaling pathway; and regulation of transcription, DNA-templated. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18945134).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRMT2	NM_206962.4	c.103T>C	p.Phe35Leu	missense_variant	4/12	ENST00000355680.8	NP_996845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRMT2	ENST00000355680.8	c.103T>C	p.Phe35Leu	missense_variant	4/12	1	NM_206962.4	ENSP00000347906.3

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151270 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151270 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73782

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

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

Oct 12, 2024

The c.103T>C (p.F35L) alteration is located in exon 4 (coding exon 2) of the PRMT2 gene. This alteration results from a T to C substitution at nucleotide position 103, causing the phenylalanine (F) at amino acid position 35 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	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.;.;T;.;T;.;T;.
Eigen	Benign	0.023
Eigen_PC	Benign	-0.0014
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.90	.;D;D;.;D;D;D;D;D
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.66	N;N;N;N;N;N;N;.;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.042
Sift	Uncertain	0.025	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.089	T;D;D;T;T;T;D;D;T
Polyphen		0.75	P;.;.;P;.;P;.;.;.
Vest4		0.33
MutPred		0.51		Gain of disorder (P = 0.1121);Gain of disorder (P = 0.1121);Gain of disorder (P = 0.1121);Gain of disorder (P = 0.1121);Gain of disorder (P = 0.1121);Gain of disorder (P = 0.1121);Gain of disorder (P = 0.1121);Gain of disorder (P = 0.1121);Gain of disorder (P = 0.1121);
MVP		0.31
MPC		1.6
ClinPred		0.49	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.66

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: rs2061317282; hg19: chr21-48063510;