chr4-99558191-C-A

Variant names:

• chr4-99558191-C-A
• rs147815779
• NM_001134665.3:c.206G>T

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.206G>T​(p.Arg69Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000414 in 1,595,934 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R69C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: TRMT10A NM_001134665.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94
• Publications: 10 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=0.23690158).

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.206G>T	p.Arg69Leu	missense	Exon 3 of 8	NP_001128137.1	Q8TBZ6
	TRMT10A	NM_001134666.3		c.206G>T	p.Arg69Leu	missense	Exon 3 of 8	NP_001128138.1	Q8TBZ6
	TRMT10A	NM_001375880.1		c.206G>T	p.Arg69Leu	missense	Exon 3 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.206G>T	p.Arg69Leu	missense	Exon 3 of 8	ENSP00000378342.2	Q8TBZ6
	TRMT10A	ENST00000273962.7	TSL:1	c.206G>T	p.Arg69Leu	missense	Exon 3 of 8	ENSP00000273962.3	Q8TBZ6
	TRMT10A	ENST00000394877.7	TSL:2	c.206G>T	p.Arg69Leu	missense	Exon 3 of 8	ENSP00000378343.3	Q8TBZ6

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152000 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000300 AC: 7 AN: 233286 AF XY: 0.0000397

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000336

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000553

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000443 AC: 64 AN: 1443934 Hom.: 0 Cov.: 30 AF XY: 0.0000320 AC XY: 23 AN XY: 717820

African (AFR) AF: 0.00 AC: 0 AN: 32024

American (AMR) AF: 0.00 AC: 0 AN: 39380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25212

East Asian (EAS) AF: 0.00 AC: 0 AN: 39468

South Asian (SAS) AF: 0.00 AC: 0 AN: 82050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.0000578 AC: 64 AN: 1107300

Other (OTH) AF: 0.00 AC: 0 AN: 59622

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152000 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74244

African (AFR) AF: 0.0000483 AC: 2 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67906

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 2

Bravo AF: 0.0000264

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

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	Uncertain	0.38
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.081	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.16
Sift	Benign	0.19	T
Sift4G	Benign	0.10	T
Polyphen		0.84	P
Vest4		0.58
MutPred		0.23		Loss of glycosylation at K73 (P = 0.0461)
MVP		0.60
MPC		0.58
ClinPred		0.47	T
GERP RS		5.8
Varity_R		0.43
gMVP		0.15
Mutation Taster		=78/22	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: rs147815779; hg19: chr4-100479348;