14-103534616-C-T

Variant names:

• chr14-103534616-C-T
• rs201788463
• NM_152307.3:c.665C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_152307.3(TRMT61A):​c.665C>T​(p.Ala222Val) variant causes a missense change. The variant allele was found at a frequency of 0.000209 in 1,606,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: TRMT61A NM_152307.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.62

Genes affected

TRMT61A (HGNC:23790): (tRNA methyltransferase 61A) Enables mRNA (adenine-N1-)-methyltransferase activity. Involved in mRNA methylation. Predicted to be located in nucleoplasm. Predicted to be part of tRNA (m1A) methyltransferase complex. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-103534616-C-T is Pathogenic according to our data. Variant chr14-103534616-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3747854.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0056594014). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRMT61A	NM_152307.3	c.665C>T	p.Ala222Val	missense_variant	Exon 4 of 4	ENST00000389749.9	NP_689520.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRMT61A	ENST00000389749.9	c.665C>T	p.Ala222Val	missense_variant	Exon 4 of 4	1	NM_152307.3	ENSP00000374399.4
TRMT61A	ENST00000299202.4	c.368C>T	p.Ala123Val	missense_variant	Exon 3 of 3	1		ENSP00000299202.4

Frequencies

GnomAD3 genomes AF: 0.000992 AC: 151 AN: 152254 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00342

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000244 AC: 59 AN: 241736 Hom.: 0 AF XY: 0.000241 AC XY: 32 AN XY: 132512

Gnomad AFR exome AF: 0.00304

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000278

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000124 AC: 180 AN: 1454008 Hom.: 0 Cov.: 31 AF XY: 0.000126 AC XY: 91 AN XY: 722184

Gnomad4 AFR exome AF: 0.00318

Gnomad4 AMR exome AF: 0.000248

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000199

Gnomad4 OTH exome AF: 0.000367

GnomAD4 genome AF: 0.00102 AC: 155 AN: 152372 Hom.: 0 Cov.: 34 AF XY: 0.00102 AC XY: 76 AN XY: 74504

Gnomad4 AFR AF: 0.00351

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000489 Hom.: 0

Bravo AF: 0.00107

ESP6500AA AF: 0.00244 AC: 10

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000265 AC: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

De Lange syndrome Pathogenic:1

Jun 01, 2024

Wonkam Laboratory, Johns Hopkins University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This variant was found in homozygous state in only affected individuals from the same family and segregates with the disease status (PP1); the amino acid alanine at position 222 on NM_152307.3 is highly conserved across a wide range of species (PP3); evidence from well-established functional studies showed decreased expression in product (PS3). In addition, this variant is absent from controls (or at extremely low frequency if recessive) in the Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.054
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.12
Sift	Benign	0.16	T
Sift4G	Benign	0.23	T
Polyphen		0.83	P
Vest4		0.14
MVP		0.31
MPC		0.67
ClinPred		0.042	T
GERP RS		3.7
Varity_R		0.20
gMVP		0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs201788463; hg19: chr14-104000953; COSMIC: COSV54569090;