rs375622926

Variant names:

• chr14-103530285-C-G
• rs375622926
• NM_152307.3:c.307C>G

Your query was ambiguous. Multiple possible variants found:

• chr14-103530285-C-G
• chr14-103530285-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_152307.3(TRMT61A):​c.307C>G​(p.Pro103Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,438,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P103S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TRMT61A NM_152307.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.61
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

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.307C>G	p.Pro103Ala	missense	Exon 2 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.307C>G	p.Pro103Ala	missense	Exon 2 of 4	ENSP00000374399.4	Q96FX7
	TRMT61A	ENST00000299202.4	TSL:1	c.34+1024C>G		intron	N/A	ENSP00000299202.4	H0Y2Q1
	TRMT61A	ENST00000896880.1		c.307C>G	p.Pro103Ala	missense	Exon 1 of 3	ENSP00000566939.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243376 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1438318 Hom.: 0 Cov.: 35 AF XY: 0.00000141 AC XY: 1 AN XY: 710242

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33134

American (AMR) AF: 0.0000226 AC: 1 AN: 44288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25730

East Asian (EAS) AF: 0.00 AC: 0 AN: 39030

South Asian (SAS) AF: 0.00 AC: 0 AN: 85398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1093512

Other (OTH) AF: 0.0000169 AC: 1 AN: 59236

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.46
Sift	Benign	0.042	D
Sift4G	Uncertain	0.051	T
Polyphen		0.94	P
Vest4		0.82
MutPred		0.72		Gain of catalytic residue at P103 (P = 0.0049)
MVP		0.59
MPC		1.4
ClinPred		0.97	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.84
Mutation Taster		=15/85	disease causing

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: rs375622926; hg19: chr14-103996622;