8-94490029-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_015496.5(VIRMA):c.5194A>G(p.Thr1732Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000909 in 1,614,030 control chromosomes in the GnomAD database, including 2 homozygotes. 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 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (2 hom.)
• Consequence: VIRMA NM_015496.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.52

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 Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, VIRMA
• BP4: Computational evidence support a benign effect (MetaRNN=0.014356494).
• BS2: High AC in GnomAd at 100 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VIRMA	NM_015496.5	c.5194A>G	p.Thr1732Ala	missense_variant	23/24	ENST00000297591.10
VIRMA	XM_047421677.1	c.4189A>G	p.Thr1397Ala	missense_variant	24/25
VIRMA	XM_047421678.1	c.4189A>G	p.Thr1397Ala	missense_variant	19/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VIRMA	ENST00000297591.10	c.5194A>G	p.Thr1732Ala	missense_variant	23/24	1	NM_015496.5	P1

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000625 AC: 157 AN: 251344 Hom.: 1 AF XY: 0.000582 AC XY: 79 AN XY: 135838

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000935 AC: 1367 AN: 1461818 Hom.: 2 Cov.: 31 AF XY: 0.000883 AC XY: 642 AN XY: 727220

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00117

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.000766 AC XY: 57 AN XY: 74442

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000967 Hom.: 0

Bravo AF: 0.000669

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000618 AC: 75

EpiCase AF: 0.00120

EpiControl AF: 0.000830

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

Jun 30, 2022

The c.5194A>G (p.T1732A) alteration is located in exon 23 (coding exon 23) of the KIAA1429 gene. This alteration results from a A to G substitution at nucleotide position 5194, causing the threonine (T) at amino acid position 1732 to be replaced by an alanine (A). 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	0.073
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.068
Sift	Benign	0.26	T
Sift4G	Benign	0.28	T
Polyphen		0.0010	B
Vest4		0.31
MVP		0.068
MPC		0.44
ClinPred		0.024	T
GERP RS		5.8
Varity_R		0.097
gMVP		0.30

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: rs147465632; hg19: chr8-95502257;