8-13006247-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020844.3(TRMT9B):c.45T>A(p.Asn15Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 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. N15D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRMT9B NM_020844.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.14

Genes affected

TRMT9B (HGNC:26725): (tRNA methyltransferase 9B (putative)) Enables tRNA methyltransferase activity. Predicted to be involved in tRNA wobble uridine modification. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

LOC124901889 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03546965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRMT9B	NM_020844.3	c.45T>A	p.Asn15Lys	missense_variant	3/5	ENST00000524591.7
LOC124901889	XR_007060825.1	n.491+8093A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRMT9B	ENST00000524591.7	c.45T>A	p.Asn15Lys	missense_variant	3/5	5	NM_020844.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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 21, 2023

The c.45T>A (p.N15K) alteration is located in exon 3 (coding exon 1) of the KIAA1456 gene. This alteration results from a T to A substitution at nucleotide position 45, causing the asparagine (N) at amino acid position 15 to be replaced by a lysine (K). 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	0.13
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.050
Dann	Benign	0.76
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.74	T;T;.;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.035	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.11	N;N;.;.;N
REVEL	Benign	0.031
Sift	Benign	0.12	T;T;.;.;T
Sift4G	Benign	0.30	T;T;T;T;T
Polyphen		0.0, 0.033	.;B;.;.;B
Vest4		0.22
MutPred		0.34		Gain of methylation at N15 (P = 0.0082);Gain of methylation at N15 (P = 0.0082);Gain of methylation at N15 (P = 0.0082);Gain of methylation at N15 (P = 0.0082);Gain of methylation at N15 (P = 0.0082);
MVP		0.014
ClinPred		0.12	T
GERP RS		-11
Varity_R		0.034
gMVP		0.25

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: rs201664403; hg19: chr8-12863756;