8-94494948-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_015496.5(VIRMA):c.4553A>T(p.Tyr1518Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000345 in 1,447,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. Y1518C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: VIRMA NM_015496.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.59

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 1 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=0.09831008).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VIRMA	NM_015496.5	c.4553A>T	p.Tyr1518Phe	missense_variant	20/24	ENST00000297591.10
VIRMA	XM_047421677.1	c.3548A>T	p.Tyr1183Phe	missense_variant	21/25
VIRMA	XM_047421678.1	c.3548A>T	p.Tyr1183Phe	missense_variant	16/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VIRMA	ENST00000297591.10	c.4553A>T	p.Tyr1518Phe	missense_variant	20/24	1	NM_015496.5	P1
VIRMA	ENST00000522263.5	c.*286A>T		3_prime_UTR_variant, NMD_transcript_variant	12/15	1
VIRMA	ENST00000521080.5	n.5488+783A>T		intron_variant, non_coding_transcript_variant		1
VIRMA	ENST00000523263.1	c.270+783A>T		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 247166 Hom.: 0 AF XY: 0.00000749 AC XY: 1 AN XY: 133558

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000166

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1447750 Hom.: 0 Cov.: 26 AF XY: 0.00000139 AC XY: 1 AN XY: 720910

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.00000824 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

Mar 07, 2024

The c.4553A>T (p.Y1518F) alteration is located in exon 20 (coding exon 20) of the KIAA1429 gene. This alteration results from a A to T substitution at nucleotide position 4553, causing the tyrosine (Y) at amino acid position 1518 to be replaced by a phenylalanine (F). 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	0.071
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	20
Dann	Benign	0.97
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.042
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.71	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.070
Sift	Benign	0.50	T
Sift4G	Benign	0.19	T
Polyphen		0.079	B
Vest4		0.30
MutPred		0.61		Loss of catalytic residue at Y1518 (P = 0.1543);
MVP		0.093
MPC		0.26
ClinPred		0.16	T
GERP RS		5.2
Varity_R		0.16
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs763006732; hg19: chr8-95507176;