chr14-103534616-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. 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. 14/22 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
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152307.3. 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
	TRMT61A	NM_152307.3	MANE Select	c.665C>T	p.Ala222Val	missense	Exon 4 of 4	NP_689520.2	Q96FX7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRMT61A	ENST00000389749.9	TSL:1 MANE Select	c.665C>T	p.Ala222Val	missense	Exon 4 of 4	ENSP00000374399.4	Q96FX7
	TRMT61A	ENST00000299202.4	TSL:1	c.368C>T	p.Ala123Val	missense	Exon 3 of 3	ENSP00000299202.4	H0Y2Q1
	TRMT61A	ENST00000896880.1		c.665C>T	p.Ala222Val	missense	Exon 3 of 3	ENSP00000566939.1

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

GnomAD2 exomes AF: 0.000244 AC: 59 AN: 241736 AF XY: 0.000241

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 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

African (AFR) AF: 0.00318 AC: 106 AN: 33294

American (AMR) AF: 0.000248 AC: 11 AN: 44324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25970

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39444

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51764

Middle Eastern (MID) AF: 0.000871 AC: 5 AN: 5738

European-Non Finnish (NFE) AF: 0.0000199 AC: 22 AN: 1107494

Other (OTH) AF: 0.000367 AC: 22 AN: 59944

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

African (AFR) AF: 0.00351 AC: 146 AN: 41594

American (AMR) AF: 0.000196 AC: 3 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000529 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

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	De Lange syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.6
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
Mutation Taster		=73/27	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: rs201788463; hg19: chr14-104000953; COSMIC: COSV54569090;