16-8635267-G-A

Position:

• chr16-8635267-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024109.4(METTL22):​c.655G>A​(p.Ala219Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 1,603,568 control chromosomes in the GnomAD database, including 53,780 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.20 (3785 hom., cov: 33)
  • Exomes 𝑓: 0.26 (49995 hom.)
• Consequence: METTL22 NM_024109.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.88

Genes affected

METTL22 (HGNC:28368): (methyltransferase 22, Kin17 lysine) This gene encodes a member of the non-histone lysine methyltransferases. It interacts with its substrate, Kin17, which is involved in DNA repair and replication and mRNA processing. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070168376).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
METTL22	NM_024109.4	c.655G>A	p.Ala219Thr	missense_variant	5/11	ENST00000381920.8	NP_077014.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
METTL22	ENST00000381920.8	c.655G>A	p.Ala219Thr	missense_variant	5/11	5	NM_024109.4	ENSP00000371345.3

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29771 AN: 151964 Hom.: 3785 Cov.: 33

Gnomad AFR AF: 0.0554

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.0934

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.200

GnomAD3 exomes AF: 0.223 AC: 54396 AN: 244294 Hom.: 6970 AF XY: 0.224 AC XY: 29762 AN XY: 132658

Gnomad AFR exome AF: 0.0507

Gnomad AMR exome AF: 0.149

Gnomad ASJ exome AF: 0.0965

Gnomad EAS exome AF: 0.370

Gnomad SAS exome AF: 0.164

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.269

Gnomad OTH exome AF: 0.216

GnomAD4 exome AF: 0.255 AC: 370453 AN: 1451486 Hom.: 49995 Cov.: 39 AF XY: 0.253 AC XY: 182320 AN XY: 720806

Gnomad4 AFR exome AF: 0.0444

Gnomad4 AMR exome AF: 0.154

Gnomad4 ASJ exome AF: 0.0958

Gnomad4 EAS exome AF: 0.347

Gnomad4 SAS exome AF: 0.160

Gnomad4 FIN exome AF: 0.243

Gnomad4 NFE exome AF: 0.276

Gnomad4 OTH exome AF: 0.235

GnomAD4 genome AF: 0.196 AC: 29768 AN: 152082 Hom.: 3785 Cov.: 33 AF XY: 0.196 AC XY: 14567 AN XY: 74338

Gnomad4 AFR AF: 0.0555

Gnomad4 AMR AF: 0.181

Gnomad4 ASJ AF: 0.0934

Gnomad4 EAS AF: 0.356

Gnomad4 SAS AF: 0.171

Gnomad4 FIN AF: 0.237

Gnomad4 NFE AF: 0.271

Gnomad4 OTH AF: 0.199

Alfa AF: 0.250 Hom.: 9774

Bravo AF: 0.187

TwinsUK AF: 0.262 AC: 972

ALSPAC AF: 0.283 AC: 1092

ESP6500AA AF: 0.0589 AC: 240

ESP6500EA AF: 0.255 AC: 2143

ExAC AF: 0.223 AC: 26995

Asia WGS AF: 0.240 AC: 834 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.0
DANN	Uncertain	1.0
DEOGEN2	Benign	0.00085	T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.88	D;D
MetaRNN	Benign	0.0070	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.24	N;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.070	N;N
REVEL	Benign	0.013
Sift	Benign	0.62	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.012	B;.
Vest4		0.096
MPC		0.016
ClinPred		0.0088	T
GERP RS		-0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025
gMVP		0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs2302607; hg19: chr16-8729124; COSMIC: COSV50838520; COSMIC: COSV50838520;