chr4-99549376-C-T

Variant names:

• chr4-99549376-C-T
• rs80053092
• NM_001134665.3:c.752-20G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001134665.3(TRMT10A):​c.752-20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0041 in 1,609,248 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (175 hom.)
• Consequence: TRMT10A NM_001134665.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.488
• Publications: 1 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 (BayesDel_noAF=-0.84).
• BP6: Variant 4-99549376-C-T is Benign according to our data. Variant chr4-99549376-C-T is described in ClinVar as Benign. ClinVar VariationId is 1562217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0624 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMT10A	NM_001134665.3	MANE Select	c.752-20G>A		intron	N/A	NP_001128137.1	Q8TBZ6
	TRMT10A	NM_001134666.3		c.752-20G>A		intron	N/A	NP_001128138.1	Q8TBZ6
	TRMT10A	NM_001375880.1		c.752-20G>A		intron	N/A	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.752-20G>A		intron	N/A	ENSP00000378342.2	Q8TBZ6
	TRMT10A	ENST00000273962.7	TSL:1	c.752-20G>A		intron	N/A	ENSP00000273962.3	Q8TBZ6
	TRMT10A	ENST00000394877.7	TSL:2	c.752-20G>A		intron	N/A	ENSP00000378343.3	Q8TBZ6

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 759 AN: 152138 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0263

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0348

Gnomad SAS AF: 0.0255

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.0152 AC: 3745 AN: 247018 AF XY: 0.0130

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.0731

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0290

Gnomad FIN exome AF: 0.0000472

Gnomad NFE exome AF: 0.000190

Gnomad OTH exome AF: 0.00664

GnomAD4 exome AF: 0.00401 AC: 5841 AN: 1456992 Hom.: 175 Cov.: 31 AF XY: 0.00414 AC XY: 2996 AN XY: 723992

African (AFR) AF: 0.000240 AC: 8 AN: 33326

American (AMR) AF: 0.0644 AC: 2869 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 26012

East Asian (EAS) AF: 0.0225 AC: 891 AN: 39582

South Asian (SAS) AF: 0.0195 AC: 1675 AN: 86038

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52918

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5746

European-Non Finnish (NFE) AF: 0.000159 AC: 176 AN: 1108596

Other (OTH) AF: 0.00352 AC: 212 AN: 60210

GnomAD4 genome AF: 0.00499 AC: 760 AN: 152256 Hom.: 11 Cov.: 32 AF XY: 0.00604 AC XY: 450 AN XY: 74452

African (AFR) AF: 0.000578 AC: 24 AN: 41554

American (AMR) AF: 0.0263 AC: 402 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.0349 AC: 181 AN: 5188

South Asian (SAS) AF: 0.0256 AC: 123 AN: 4812

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68012

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00191 Hom.: 0

Bravo AF: 0.00768

Asia WGS AF: 0.0280 AC: 96 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.3
DANN	Benign	0.49
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs80053092; hg19: chr4-100470533; COSMIC: COSV56745107; COSMIC: COSV56745107;