8-94491593-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_015496.5(VIRMA):c.5125C>T(p.Pro1709Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,858 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 (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: VIRMA NM_015496.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

Genes affected

VIRMA (HGNC:24500): (vir like m6A methyltransferase associated) Enables RNA binding activity. Involved in mRNA alternative polyadenylation and mRNA methylation. Located in cytosol and nuclear speck. Colocalizes with RNA N6-methyladenosine methyltransferase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, VIRMA
• BP4: Computational evidence support a benign effect (MetaRNN=0.35688102).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VIRMA	NM_015496.5	c.5125C>T	p.Pro1709Ser	missense_variant	22/24	ENST00000297591.10
VIRMA	XM_047421677.1	c.4120C>T	p.Pro1374Ser	missense_variant	23/25
VIRMA	XM_047421678.1	c.4120C>T	p.Pro1374Ser	missense_variant	18/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VIRMA	ENST00000297591.10	c.5125C>T	p.Pro1709Ser	missense_variant	22/24	1	NM_015496.5	P1
VIRMA	ENST00000521080.5	n.5972C>T		non_coding_transcript_exon_variant	8/10	1
VIRMA	ENST00000522263.5	c.*541+1059C>T		intron_variant, NMD_transcript_variant		1
VIRMA	ENST00000517624.1	c.107+1059C>T		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458858 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

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 10, 2023

The c.5125C>T (p.P1709S) alteration is located in exon 22 (coding exon 22) of the KIAA1429 gene. This alteration results from a C to T substitution at nucleotide position 5125, causing the proline (P) at amino acid position 1709 to be replaced by a serine (S). 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	0.60
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.033	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.019	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.32		Gain of MoRF binding (P = 0.054);
MVP		0.10
MPC		0.92
ClinPred		0.92	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.74

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: rs745569493; hg19: chr8-95503821;