chr4-99549194-T-TCACTGTC

Position:

• chr4-99549194-T-TCACTGTC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001134665.3(TRMT10A):​c.913_914insGACAGTG​(p.Asp305GlyfsTer3) variant causes a stop gained, frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRMT10A NM_001134665.3 stop_gained, frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

Genes affected

TRMT10A (HGNC:28403): (tRNA methyltransferase 10A) This gene encodes a protein that belongs to the tRNA (Guanine-1)-methyltransferase family. A similar gene in yeast modifies several different tRNA species. Mutations in this gene are associated with microcephaly, short stature, and impaired glucose metabolism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.105 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRMT10A	NM_001134665.3	c.913_914insGACAGTG	p.Asp305GlyfsTer3	stop_gained, frameshift_variant	8/8	ENST00000394876.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRMT10A	ENST00000394876.7	c.913_914insGACAGTG	p.Asp305GlyfsTer3	stop_gained, frameshift_variant	8/8	1	NM_001134665.3	P1
TRMT10A	ENST00000273962.7	c.913_914insGACAGTG	p.Asp305GlyfsTer3	stop_gained, frameshift_variant	8/8	1		P1
TRMT10A	ENST00000394877.7	c.913_914insGACAGTG	p.Asp305GlyfsTer3	stop_gained, frameshift_variant	8/8	2		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 06, 2022

This sequence change creates a premature translational stop signal (p.Asp305Glyfs*3) in the TRMT10A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 35 amino acid(s) of the TRMT10A protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TRMT10A-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-100470351;