chr4-99549314-T-C

Variant names:

• chr4-99549314-T-C
• rs747861253
• NM_001134665.3:c.794A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001134665.3(TRMT10A):​c.794A>G​(p.Gln265Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: 0.0000055 (0 hom.)
• Consequence: TRMT10A NM_001134665.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.71
• Publications: 0 publications found

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]

TRMT10A Gene-Disease associations (from GenCC):

• microcephaly, short stature, and impaired glucose metabolism 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• primary microcephaly-mild intellectual disability-young-onset diabetes syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11049017).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134665.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMT10A	NM_001134665.3	MANE Select	c.794A>G	p.Gln265Arg	missense	Exon 8 of 8	NP_001128137.1	Q8TBZ6
	TRMT10A	NM_001134666.3		c.794A>G	p.Gln265Arg	missense	Exon 8 of 8	NP_001128138.1	Q8TBZ6
	TRMT10A	NM_001375880.1		c.794A>G	p.Gln265Arg	missense	Exon 8 of 8	NP_001362809.1	Q8TBZ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMT10A	ENST00000394876.7	TSL:1 MANE Select	c.794A>G	p.Gln265Arg	missense	Exon 8 of 8	ENSP00000378342.2	Q8TBZ6
	TRMT10A	ENST00000273962.7	TSL:1	c.794A>G	p.Gln265Arg	missense	Exon 8 of 8	ENSP00000273962.3	Q8TBZ6
	TRMT10A	ENST00000394877.7	TSL:2	c.794A>G	p.Gln265Arg	missense	Exon 8 of 8	ENSP00000378343.3	Q8TBZ6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249856 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461822 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000671 AC: 3 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111974

Other (OTH) AF: 0.0000331 AC: 2 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	22
DANN	Benign	0.78
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.78	N
PhyloP100		3.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.051
Sift	Benign	0.62	T
Sift4G	Benign	0.15	T
Polyphen		0.026	B
Vest4		0.085
MutPred		0.38		Loss of glycosylation at T270 (P = 0.0564)
MVP		0.22
MPC		0.22
ClinPred		0.27	T
GERP RS		5.9
Varity_R		0.51
gMVP		0.30
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs747861253; hg19: chr4-100470471;