rs748265622

Variant names:

• chr19-13104975-G-A
• rs748265622
• NM_001136035.4:c.1940C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-13104975-G-A
• chr19-13104975-G-C
• chr19-13104975-G-T

Variant summary

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

The NM_001136035.4(TRMT1):​c.1940C>T​(p.Pro647Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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: 0.0000021 (0 hom.)
• Consequence: TRMT1 NM_001136035.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.935
• Publications: 1 publications found

Genes affected

TRMT1 (HGNC:25980): (tRNA methyltransferase 1) This gene encodes a tRNA-modifying enzyme that acts as a dimethyltransferase, modifying a single guanine residue at position 26 of the tRNA. The encoded enzyme has both mono- and dimethylase activity when exogenously expressed, and uses S-adenosyl methionine as a methyl donor. The C-terminal region of the encoded protein has both a zinc finger motif, and an arginine/proline-rich region. Mutations in this gene have been implicated in autosomal recessive intellectual disorder (ARID). Alternative splicing results in multiple transcript variants encoding different isoforms. There is a pseudogene of this gene on the X chromosome. [provided by RefSeq, May 2017]

TRMT1 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, autosomal recessive 68

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000304024 (HGNC:):

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=0.11494437).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136035.4. 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
	TRMT1	NM_001136035.4	MANE Select	c.1940C>T	p.Pro647Leu	missense	Exon 17 of 17	NP_001129507.1	Q9NXH9-1
	TRMT1	NM_017722.5		c.1940C>T	p.Pro647Leu	missense	Exon 16 of 16	NP_060192.1	Q9NXH9-1
	TRMT1	NM_001142554.3		c.1853C>T	p.Pro618Leu	missense	Exon 15 of 15	NP_001136026.1	Q9NXH9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMT1	ENST00000357720.9	TSL:2 MANE Select	c.1940C>T	p.Pro647Leu	missense	Exon 17 of 17	ENSP00000350352.4	Q9NXH9-1
	TRMT1	ENST00000437766.5	TSL:1	c.1940C>T	p.Pro647Leu	missense	Exon 16 of 16	ENSP00000416149.1	Q9NXH9-1
	TRMT1	ENST00000221504.12	TSL:1	c.1853C>T	p.Pro618Leu	missense	Exon 15 of 15	ENSP00000221504.7	Q9NXH9-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250868 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461598 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727068

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53190

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111964

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.88
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.94
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.071
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.020	D
Polyphen		0.14	B
Vest4		0.29
MutPred		0.16		Loss of glycosylation at P647 (P = 0.0326)
MVP		0.46
MPC		0.14
ClinPred		0.16	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.30
Mutation Taster		=96/4	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: rs748265622; hg19: chr19-13215789; COSMIC: COSV53399792; COSMIC: COSV53399792;