rs17650204

chr1-171785931-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_015935.5(METTL13):c.966A>G(p.Lys322=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0896 in 1,613,564 control chromosomes in the GnomAD database, including 7,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.072 (556 hom., cov: 32)
  • Exomes 𝑓: 0.092 (6816 hom.)
• Consequence: METTL13 NM_015935.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.26

Genes affected

METTL13 (HGNC:24248): (methyltransferase 13, eEF1A N-terminus and K55) Predicted to enable methyltransferase activity. Involved in negative regulation of cell cycle G1/S phase transition and negative regulation of transcription by RNA polymerase II. Predicted to be located in mitochondrion and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 1-171785931-A-G is Benign according to our data. Variant chr1-171785931-A-G is described in ClinVar as [Benign]. Clinvar id is 3055433.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=3.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
METTL13	NM_015935.5	c.966A>G	p.Lys322=	synonymous_variant	3/8	ENST00000361735.4
METTL13	NM_014955.3	c.708A>G	p.Lys236=	synonymous_variant	3/8
METTL13	NM_001007239.2	c.498A>G	p.Lys166=	synonymous_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
METTL13	ENST00000361735.4	c.966A>G	p.Lys322=	synonymous_variant	3/8	1	NM_015935.5	P1
METTL13	ENST00000367737.9	c.498A>G	p.Lys166=	synonymous_variant	3/8	1
METTL13	ENST00000362019.7	c.708A>G	p.Lys236=	synonymous_variant	3/8	2
METTL13	ENST00000485629.1	n.610A>G		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.0717 AC: 10903 AN: 152068 Hom.: 556 Cov.: 32

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.0554

Gnomad ASJ AF: 0.0966

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0272

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.0665

GnomAD3 exomes AF: 0.0750 AC: 18791 AN: 250640 Hom.: 952 AF XY: 0.0761 AC XY: 10311 AN XY: 135516

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.0371

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0298

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.0824

GnomAD4 exome AF: 0.0915 AC: 133722 AN: 1461378 Hom.: 6816 Cov.: 31 AF XY: 0.0906 AC XY: 65879 AN XY: 726948

Gnomad4 AFR exome AF: 0.0130

Gnomad4 AMR exome AF: 0.0387

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0310

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.103

Gnomad4 OTH exome AF: 0.0845

GnomAD4 genome AF: 0.0716 AC: 10904 AN: 152186 Hom.: 556 Cov.: 32 AF XY: 0.0708 AC XY: 5267 AN XY: 74390

Gnomad4 AFR AF: 0.0164

Gnomad4 AMR AF: 0.0554

Gnomad4 ASJ AF: 0.0966

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0272

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.0658

Alfa AF: 0.0985 Hom.: 1965

Bravo AF: 0.0635

Asia WGS AF: 0.0180 AC: 63 AN: 3478

EpiCase AF: 0.107

EpiControl AF: 0.102

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

METTL13-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	10
Dann	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs17650204; hg19: chr1-171755071;