1-156733033-G-T

Variant names:

• chr1-156733033-G-T
• rs367820508
• NM_015997.4:c.478G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015997.4(METTL25B):​c.478G>T​(p.Val160Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,786 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. 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. V160M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: METTL25B NM_015997.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.51
• Publications: 5 publications found

Genes affected

METTL25B (HGNC:24273): (methyltransferase like 25B) Predicted to enable rRNA (adenine-N6,N6-)-dimethyltransferase activity. Predicted to be involved in rRNA methylation. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35853308).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015997.4. 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
	METTL25B	NM_015997.4	MANE Select	c.478G>T	p.Val160Leu	missense	Exon 4 of 8	NP_057081.3
	METTL25B	NM_001142560.2		c.478G>T	p.Val160Leu	missense	Exon 4 of 7	NP_001136032.1	Q96FB5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	METTL25B	ENST00000368216.9	TSL:1 MANE Select	c.478G>T	p.Val160Leu	missense	Exon 4 of 8	ENSP00000357199.4	Q96FB5-1
	METTL25B	ENST00000917461.1		c.478G>T	p.Val160Leu	missense	Exon 4 of 8	ENSP00000587520.1
	METTL25B	ENST00000892486.1		c.478G>T	p.Val160Leu	missense	Exon 4 of 8	ENSP00000562545.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251382 AF XY: 0.00000736

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: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727192

⚠️ 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: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44708

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111952

Other (OTH) AF: 0.00 AC: 0 AN: 60386

⚠️ 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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.043
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.088
Sift	Benign	0.065	T
Sift4G	Uncertain	0.021	D
Polyphen		0.052	B
Vest4		0.61
MutPred		0.56		Loss of sheet (P = 0.1907)
MVP		0.52
MPC		0.30
ClinPred		0.71	D
GERP RS		3.0
Varity_R		0.12
gMVP		0.49
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs367820508; hg19: chr1-156702825;