chr1-171783899-A-G

Variant names:

• chr1-171783899-A-G
• rs2232816
• NM_015935.5:c.313A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_015935.5(METTL13):​c.313A>G​(p.Met105Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,613,946 control chromosomes in the GnomAD database, including 65,318 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.29 (6720 hom., cov: 32)
  • Exomes 𝑓: 0.28 (58598 hom.)
• Consequence: METTL13 NM_015935.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.54
• Publications: 34 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8820167E-4).
• BP6: Variant 1-171783899-A-G is Benign according to our data. Variant chr1-171783899-A-G is described in ClinVar as [Benign]. Clinvar id is 3060395.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL13	NM_015935.5	c.313A>G	p.Met105Val	missense_variant	Exon 2 of 8	ENST00000361735.4	NP_057019.3
METTL13	NM_014955.3	c.55A>G	p.Met19Val	missense_variant	Exon 2 of 8		NP_055770.1
METTL13	NM_001007239.2	c.313A>G	p.Met105Val	missense_variant	Exon 2 of 8		NP_001007240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
METTL13	ENST00000361735.4	c.313A>G	p.Met105Val	missense_variant	Exon 2 of 8	1	NM_015935.5	ENSP00000354920.3
METTL13	ENST00000367737.9	c.313A>G	p.Met105Val	missense_variant	Exon 2 of 8	1		ENSP00000356711.5
METTL13	ENST00000362019.7	c.55A>G	p.Met19Val	missense_variant	Exon 2 of 8	2		ENSP00000355393.3
METTL13	ENST00000485629.1	n.425A>G		non_coding_transcript_exon_variant	Exon 3 of 4	5

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44709 AN: 151938 Hom.: 6716 Cov.: 32

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.526

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.302

GnomAD2 exomes AF: 0.288 AC: 72392 AN: 251452 AF XY: 0.282

Gnomad AFR exome AF: 0.310

Gnomad AMR exome AF: 0.278

Gnomad ASJ exome AF: 0.367

Gnomad EAS exome AF: 0.529

Gnomad FIN exome AF: 0.291

Gnomad NFE exome AF: 0.265

Gnomad OTH exome AF: 0.290

GnomAD4 exome AF: 0.277 AC: 405133 AN: 1461890 Hom.: 58598 Cov.: 50 AF XY: 0.275 AC XY: 200001 AN XY: 727246

African (AFR) AF: 0.315 AC: 10542 AN: 33480

American (AMR) AF: 0.278 AC: 12454 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 9389 AN: 26136

East Asian (EAS) AF: 0.565 AC: 22428 AN: 39700

South Asian (SAS) AF: 0.201 AC: 17313 AN: 86258

European-Finnish (FIN) AF: 0.291 AC: 15552 AN: 53420

Middle Eastern (MID) AF: 0.294 AC: 1694 AN: 5768

European-Non Finnish (NFE) AF: 0.268 AC: 298096 AN: 1112008

Other (OTH) AF: 0.292 AC: 17665 AN: 60396

GnomAD4 genome AF: 0.294 AC: 44738 AN: 152056 Hom.: 6720 Cov.: 32 AF XY: 0.296 AC XY: 21992 AN XY: 74316

African (AFR) AF: 0.308 AC: 12789 AN: 41480

American (AMR) AF: 0.300 AC: 4590 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 1200 AN: 3466

East Asian (EAS) AF: 0.526 AC: 2714 AN: 5156

South Asian (SAS) AF: 0.197 AC: 951 AN: 4816

European-Finnish (FIN) AF: 0.301 AC: 3184 AN: 10586

Middle Eastern (MID) AF: 0.329 AC: 96 AN: 292

European-Non Finnish (NFE) AF: 0.271 AC: 18406 AN: 67950

Other (OTH) AF: 0.304 AC: 640 AN: 2106

Alfa AF: 0.280 Hom.: 24134

Bravo AF: 0.296

TwinsUK AF: 0.266 AC: 985

ALSPAC AF: 0.269 AC: 1038

ESP6500AA AF: 0.310 AC: 1364

ESP6500EA AF: 0.272 AC: 2340

ExAC AF: 0.286 AC: 34682

EpiCase AF: 0.259

EpiControl AF: 0.265

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

METTL13-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.013	.;.;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.66	T;T;T
MetaRNN	Benign	0.00019	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.080	.;N;N
PhyloP100		3.5
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.17	N;N;N
REVEL	Benign	0.059
Sift	Benign	0.97	T;T;T
Sift4G	Benign	0.87	T;T;T
Polyphen		0.023, 0.012	.;B;B
Vest4		0.14
MPC		0.22
ClinPred		0.013	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.075
gMVP		0.51
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2232816; hg19: chr1-171753039; COSMIC: COSV62282627; COSMIC: COSV62282627;