chr18-2554671-T-C

Variant names:

• chr18-2554671-T-C
• rs141410214
• NM_022840.5:c.827A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_022840.5(METTL4):​c.827A>G​(p.Asn276Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000488 in 1,601,312 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (4 hom.)
• Consequence: METTL4 NM_022840.5 missense, splice_region
• Scores: Splicing: ADA: 0.0003994
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11
• Publications: 0 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01065594).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL4	NM_022840.5	c.827A>G	p.Asn276Ser	missense_variant, splice_region_variant	Exon 4 of 9	ENST00000574538.2	NP_073751.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
METTL4	ENST00000574538.2	c.827A>G	p.Asn276Ser	missense_variant, splice_region_variant	Exon 4 of 9	1	NM_022840.5	ENSP00000458290.1

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000452 AC: 108 AN: 238852 AF XY: 0.000368

Gnomad AFR exome AF: 0.0000672

Gnomad AMR exome AF: 0.000658

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000650

Gnomad NFE exome AF: 0.000619

Gnomad OTH exome AF: 0.000689

GnomAD4 exome AF: 0.000484 AC: 702 AN: 1449070 Hom.: 4 Cov.: 30 AF XY: 0.000500 AC XY: 361 AN XY: 721564

African (AFR) AF: 0.0000313 AC: 1 AN: 31934

American (AMR) AF: 0.000878 AC: 35 AN: 39866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25880

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85114

European-Finnish (FIN) AF: 0.000680 AC: 36 AN: 52910

Middle Eastern (MID) AF: 0.000204 AC: 1 AN: 4900

European-Non Finnish (NFE) AF: 0.000545 AC: 605 AN: 1109100

Other (OTH) AF: 0.000351 AC: 21 AN: 59764

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74454

African (AFR) AF: 0.0000722 AC: 3 AN: 41570

American (AMR) AF: 0.000588 AC: 9 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 67968

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000565 Hom.: 1

Bravo AF: 0.000540

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000941 AC: 8

ExAC AF: 0.000495 AC: 60

EpiCase AF: 0.000927

EpiControl AF: 0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.827A>G (p.N276S) alteration is located in exon 4 (coding exon 3) of the METTL4 gene. This alteration results from a A to G substitution at nucleotide position 827, causing the asparagine (N) at amino acid position 276 to be replaced by a serine (S). 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	0.085
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0050	.;T
Eigen	Benign	0.078
Eigen_PC	Benign	0.079
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.7	.;M
PhyloP100		1.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.9	N;.
REVEL	Benign	0.068
Sift	Benign	0.059	T;.
Sift4G	Uncertain	0.039	D;T
Polyphen		0.93	.;P
Vest4		0.18
MVP		0.71
MPC		0.079
ClinPred		0.049	T
GERP RS		1.8
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.049
gMVP		0.16
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00040
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.010		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: rs141410214; hg19: chr18-2554670;