4-99558191-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001134665.3(TRMT10A):​c.206G>A​(p.Arg69His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,596,038 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). 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 0.0026 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (6 hom.)
• Consequence: TRMT10A NM_001134665.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00686568).
• BP6: Variant 4-99558191-C-T is Benign according to our data. Variant chr4-99558191-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 437058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00264 (401/152114) while in subpopulation NFE AF = 0.00348 (236/67896). AF 95% confidence interval is 0.00311. There are 5 homozygotes in GnomAd4. There are 228 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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>A	p.Arg69His	missense	Exon 3 of 8	NP_001128137.1	Q8TBZ6
	TRMT10A	NM_001134666.3		c.206G>A	p.Arg69His	missense	Exon 3 of 8	NP_001128138.1	Q8TBZ6
	TRMT10A	NM_001375880.1		c.206G>A	p.Arg69His	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>A	p.Arg69His	missense	Exon 3 of 8	ENSP00000378342.2	Q8TBZ6
	TRMT10A	ENST00000273962.7	TSL:1	c.206G>A	p.Arg69His	missense	Exon 3 of 8	ENSP00000273962.3	Q8TBZ6
	TRMT10A	ENST00000394877.7	TSL:2	c.206G>A	p.Arg69His	missense	Exon 3 of 8	ENSP00000378343.3	Q8TBZ6

Frequencies

GnomAD3 genomes AF: 0.00263 AC: 400 AN: 151996 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00348

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00257 AC: 600 AN: 233286 AF XY: 0.00268

Gnomad AFR exome AF: 0.000379

Gnomad AMR exome AF: 0.000437

Gnomad ASJ exome AF: 0.00134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00974

Gnomad NFE exome AF: 0.00316

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00244 AC: 3523 AN: 1443924 Hom.: 6 Cov.: 30 AF XY: 0.00243 AC XY: 1745 AN XY: 717820

African (AFR) AF: 0.000375 AC: 12 AN: 32024

American (AMR) AF: 0.000559 AC: 22 AN: 39380

Ashkenazi Jewish (ASJ) AF: 0.00182 AC: 46 AN: 25212

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

South Asian (SAS) AF: 0.000390 AC: 32 AN: 82050

European-Finnish (FIN) AF: 0.00866 AC: 461 AN: 53204

Middle Eastern (MID) AF: 0.00141 AC: 8 AN: 5674

European-Non Finnish (NFE) AF: 0.00253 AC: 2798 AN: 1107290

Other (OTH) AF: 0.00242 AC: 144 AN: 59622

GnomAD4 genome AF: 0.00264 AC: 401 AN: 152114 Hom.: 5 Cov.: 33 AF XY: 0.00307 AC XY: 228 AN XY: 74368

African (AFR) AF: 0.000337 AC: 14 AN: 41548

American (AMR) AF: 0.00111 AC: 17 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0115 AC: 122 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00348 AC: 236 AN: 67896

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00263 Hom.: 2

Bravo AF: 0.00153

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00266 AC: 323

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	TRMT10A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.19
Sift	Benign	0.17	T
Sift4G	Benign	0.064	T
Polyphen		0.080	B
Vest4		0.34
MVP		0.60
MPC		0.19
ClinPred		0.034	T
GERP RS		5.8
Varity_R		0.33
gMVP		0.10
Mutation Taster		=99/1	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; COSMIC: COSV104565001; COSMIC: COSV104565001;