chr4-99554903-C-T

Variant names:

• chr4-99554903-C-T
• rs1491233
• NM_001134665.3:c.496-969G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001134665.3(TRMT10A):​c.496-969G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.595 in 151,952 control chromosomes in the GnomAD database, including 30,238 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.59 (30238 hom., cov: 31)
• Consequence: TRMT10A NM_001134665.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.79
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.888 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMT10A	NM_001134665.3	MANE Select	c.496-969G>A		intron	N/A	NP_001128137.1
	TRMT10A	NM_001134666.3		c.496-969G>A		intron	N/A	NP_001128138.1
	TRMT10A	NM_001375880.1		c.496-969G>A		intron	N/A	NP_001362809.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMT10A	ENST00000394876.7	TSL:1 MANE Select	c.496-969G>A		intron	N/A	ENSP00000378342.2
	TRMT10A	ENST00000273962.7	TSL:1	c.496-969G>A		intron	N/A	ENSP00000273962.3
	TRMT10A	ENST00000394877.7	TSL:2	c.496-969G>A		intron	N/A	ENSP00000378343.3

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90286 AN: 151834 Hom.: 30196 Cov.: 31

Gnomad AFR AF: 0.895

Gnomad AMI AF: 0.608

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.704

Gnomad EAS AF: 0.771

Gnomad SAS AF: 0.617

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.600

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.595 AC: 90369 AN: 151952 Hom.: 30238 Cov.: 31 AF XY: 0.588 AC XY: 43683 AN XY: 74244

African (AFR) AF: 0.895 AC: 37146 AN: 41488

American (AMR) AF: 0.471 AC: 7181 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 2438 AN: 3464

East Asian (EAS) AF: 0.771 AC: 3987 AN: 5170

South Asian (SAS) AF: 0.613 AC: 2955 AN: 4820

European-Finnish (FIN) AF: 0.305 AC: 3210 AN: 10520

Middle Eastern (MID) AF: 0.644 AC: 188 AN: 292

European-Non Finnish (NFE) AF: 0.463 AC: 31440 AN: 67918

Other (OTH) AF: 0.603 AC: 1271 AN: 2108

Alfa AF: 0.500 Hom.: 10352

Bravo AF: 0.617

Asia WGS AF: 0.645 AC: 2238 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.036
DANN	Benign	0.41
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs1491233; hg19: chr4-100476060;