8-94492798-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_015496.5(VIRMA):c.4662A>C(p.Glu1554Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,460,962 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: VIRMA NM_015496.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.513

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 Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, VIRMA
• BP4: Computational evidence support a benign effect (MetaRNN=0.13960445).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VIRMA	NM_015496.5	c.4662A>C	p.Glu1554Asp	missense_variant	21/24	ENST00000297591.10
VIRMA	XM_047421677.1	c.3657A>C	p.Glu1219Asp	missense_variant	22/25
VIRMA	XM_047421678.1	c.3657A>C	p.Glu1219Asp	missense_variant	17/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VIRMA	ENST00000297591.10	c.4662A>C	p.Glu1554Asp	missense_variant	21/24	1	NM_015496.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250628 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135484

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1460962 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 726794

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: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

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

Apr 13, 2023

The c.4662A>C (p.E1554D) alteration is located in exon 21 (coding exon 21) of the KIAA1429 gene. This alteration results from a A to C substitution at nucleotide position 4662, causing the glutamic acid (E) at amino acid position 1554 to be replaced by an aspartic acid (D). 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	0.074
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	15
Dann	Uncertain	1.0
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.77	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.16
Sift	Benign	0.13	T
Sift4G	Uncertain	0.0050	D
Polyphen		0.73	P
Vest4		0.24
MutPred		0.17		Gain of ubiquitination at K1549 (P = 0.115);
MVP		0.093
MPC		0.26
ClinPred		0.13	T
GERP RS		0.40
Varity_R		0.056
gMVP		0.26

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: rs772231079; hg19: chr8-95505026; COSMIC: COSV52590344; COSMIC: COSV52590344;