4-8441363-G-A

Position:

• chr4-8441363-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001350233.2(TRMT44):​c.-154G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000796 in 1,382,416 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: 33)
  • Exomes 𝑓: 0.0000080 (0 hom.)
• Consequence: TRMT44 NM_001350233.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.584

Genes affected

TRMT44 (HGNC:26653): (tRNA methyltransferase 44 homolog) The protein encoded by this gene is a putative tRNA methyltransferase found in the cytoplasm. Defects in this gene may be a cause of partial epilepsy with pericentral spikes (PEPS), but that has not been proven definitively. [provided by RefSeq, May 2012]

TRMT44 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.121192545).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRMT44	NM_152544.3	c.541G>A	p.Val181Met	missense_variant	1/11	ENST00000389737.5	NP_689757.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRMT44	ENST00000389737.5	c.541G>A	p.Val181Met	missense_variant	1/11	5	NM_152544.3	ENSP00000374387.4
TRMT44	ENST00000513449.6	c.-76+2321G>A		intron_variant		1		ENSP00000424643.2
TRMT44	ENST00000504134.1	c.400G>A	p.Val134Met	missense_variant	1/2	3		ENSP00000434207.1
TRMT44	ENST00000528167.1	n.559G>A		non_coding_transcript_exon_variant	1/3	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000796 AC: 11 AN: 1382416 Hom.: 0 Cov.: 31 AF XY: 0.00000440 AC XY: 3 AN XY: 681862

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: 0.0000102

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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 20, 2023

The c.541G>A (p.V181M) alteration is located in exon 1 (coding exon 1) of the TRMT44 gene. This alteration results from a G to A substitution at nucleotide position 541, causing the valine (V) at amino acid position 181 to be replaced by a methionine (M). 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	0.15
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.029
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.058	T
Vest4		0.17
MutPred		0.49		Loss of sheet (P = 0.0315);
MVP		0.14
MPC		0.081
ClinPred		0.88	D
GERP RS		1.3
Varity_R		0.043
gMVP		0.16

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: rs1724679914; hg19: chr4-8443090;