18-2544197-G-A

Variant names:

• chr18-2544197-G-A
• rs146667523
• NM_022840.5:c.1271C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_022840.5(METTL4):​c.1271C>T​(p.Ala424Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000153 in 1,596,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: METTL4 NM_022840.5 missense, splice_region
• Scores: Splicing: ADA: 0.9897
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17
• Publications: 4 publications found

Genes affected

METTL4 (HGNC:24726): (methyltransferase 4, N6-adenosine) Enables RNA methyltransferase activity and site-specific DNA-methyltransferase (adenine-specific) activity. Involved in nucleic acid metabolic process; regulation of RNA metabolic process; and regulation of mitochondrial DNA replication. Located in cytosol; mitochondrial matrix; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL4	NM_022840.5	c.1271C>T	p.Ala424Val	missense_variant, splice_region_variant	Exon 8 of 9	ENST00000574538.2	NP_073751.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
METTL4	ENST00000574538.2	c.1271C>T	p.Ala424Val	missense_variant, splice_region_variant	Exon 8 of 9	1	NM_022840.5	ENSP00000458290.1
METTL4	ENST00000573134.1	n.3572C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 7	1
METTL4	ENST00000319888.10	c.1181+456C>T		intron_variant	Intron 7 of 7	5		ENSP00000320349.6
METTL4	ENST00000576251.5	c.267+3158C>T		intron_variant	Intron 3 of 3	2		ENSP00000460774.1

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152006 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000840 AC: 20 AN: 238034 AF XY: 0.0000777

Gnomad AFR exome AF: 0.0000625

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: 0.000163

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.000159 AC: 230 AN: 1444120 Hom.: 0 Cov.: 29 AF XY: 0.000152 AC XY: 109 AN XY: 718478

African (AFR) AF: 0.00 AC: 0 AN: 32682

American (AMR) AF: 0.0000247 AC: 1 AN: 40458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25458

East Asian (EAS) AF: 0.00 AC: 0 AN: 39472

South Asian (SAS) AF: 0.00 AC: 0 AN: 82602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.000200 AC: 221 AN: 1104836

Other (OTH) AF: 0.000134 AC: 8 AN: 59684

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 152006 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74214

African (AFR) AF: 0.0000725 AC: 3 AN: 41372

American (AMR) AF: 0.00 AC: 0 AN: 15256

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000168 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000115 AC: 14

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1271C>T (p.A424V) alteration is located in exon 8 (coding exon 7) of the METTL4 gene. This alteration results from a C to T substitution at nucleotide position 1271, causing the alanine (A) at amino acid position 424 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0038	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.3	L
PhyloP100		6.2
PrimateAI	Uncertain	0.52	T
Sift4G	Benign	0.20	T
Polyphen		0.58	P
Vest4		0.39
MVP		0.55
MPC		0.19
ClinPred		0.13	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.26
gMVP		0.36
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.77
SpliceAI score (max)		0.030		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: rs146667523; hg19: chr18-2544196;