12-3553653-C-G

Variant names:

• chr12-3553653-C-G
• rs757296672
• NM_019854.5:c.420C>G

Variant summary

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

The NM_019854.5(PRMT8):​c.420C>G​(p.Ile140Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRMT8 NM_019854.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.928

Genes affected

PRMT8 (HGNC:5188): (protein arginine methyltransferase 8) Arginine methylation is a widespread posttranslational modification mediated by arginine methyltransferases, such as PRMT8. Arginine methylation is involved in a number of cellular processes, including DNA repair, RNA transcription, signal transduction, protein compartmentalization, and possibly protein translation (Lee et al., 2005 [PubMed 16051612]).[supplied by OMIM, Mar 2008]

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, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRMT8	NM_019854.5	c.420C>G	p.Ile140Met	missense_variant, splice_region_variant	Exon 4 of 10	ENST00000382622.4	NP_062828.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRMT8	ENST00000382622.4	c.420C>G	p.Ile140Met	missense_variant, splice_region_variant	Exon 4 of 10	1	NM_019854.5	ENSP00000372067.3
PRMT8	ENST00000452611.6	c.393C>G	p.Ile131Met	missense_variant, splice_region_variant	Exon 4 of 10	1		ENSP00000414507.2
PRMT8	ENST00000261252.4	n.971C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 12	2
PRMT8	ENST00000543701.5	n.4346C>G		non_coding_transcript_exon_variant	Exon 3 of 9	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.420C>G (p.I140M) alteration is located in exon 4 (coding exon 4) of the PRMT8 gene. This alteration results from a C to G substitution at nucleotide position 420, causing the isoleucine (I) at amino acid position 140 to be replaced by a methionine (M). 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	0.62
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.3	.;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.016	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		0.98	D;P
Vest4		0.87
MutPred		0.66		.;Gain of disorder (P = 0.0768);
MVP		0.59
MPC		2.4
ClinPred		0.97	D
GERP RS		-5.1
Varity_R		0.59
gMVP		0.94

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: rs757296672; hg19: chr12-3662819;