Variant chr2-207613143-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001127395.5(METTL21A):c.560T>C(p.Leu187Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,461,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

METTL21A
NM_001127395.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.79

Variant links:

Genes affected

METTL21A (HGNC:30476): (methyltransferase 21A, HSPA lysine) Enables ATPase binding activity; Hsp70 protein binding activity; and protein-lysine N-methyltransferase activity. Involved in peptidyl-lysine methylation. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

METTL21A links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
METTL21A	NM_001127395.5 linkuse as main transcript	c.560T>C	p.Leu187Pro	missense_variant	4/4	ENST00000411432.6	NP_001120867.1	Q8WXB1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
METTL21A	ENST00000411432.6 linkuse as main transcript	c.560T>C	p.Leu187Pro	missense_variant	4/4	2	NM_001127395.5	ENSP00000415115.1		Q8WXB1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250916

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135606

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1461438

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726988

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2024

The c.560T>C (p.L187P) alteration is located in exon 4 (coding exon 3) of the METTL21A gene. This alteration results from a T to C substitution at nucleotide position 560, causing the leucine (L) at amino acid position 187 to be replaced by a proline (P). 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

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.060

T;T;T;T;T;T

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.76

T;.;T;.;.;.

M_CAP

Benign

0.072

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D

MetaSVM

Benign

-0.69

MutationAssessor

Pathogenic

3.3

M;M;.;M;M;M

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.1

D;D;D;D;D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;D

Polyphen

1.0

D;D;.;D;D;D

Vest4

0.85

MutPred

0.89

Loss of stability (P = 0.0465);Loss of stability (P = 0.0465);.;Loss of stability (P = 0.0465);Loss of stability (P = 0.0465);Loss of stability (P = 0.0465);

MVP

0.59

MPC

1.0

ClinPred

0.99

GERP RS

3.8

Varity_R

0.99

gMVP

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over