chr2-207613387-C-G

Position:

• chr2-207613387-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001127395.5(METTL21A):​c.316G>C​(p.Val106Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V106I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: METTL21A NM_001127395.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.11

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
METTL21A	NM_001127395.5	c.316G>C	p.Val106Leu	missense_variant	4/4	ENST00000411432.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
METTL21A	ENST00000411432.6	c.316G>C	p.Val106Leu	missense_variant	4/4	2	NM_001127395.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.316G>C (p.V106L) alteration is located in exon 4 (coding exon 3) of the METTL21A gene. This alteration results from a G to C substitution at nucleotide position 316, causing the valine (V) at amino acid position 106 to be replaced by a leucine (L). 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	Uncertain	0.44
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T;T;T;T;T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;.;D;.;.;.
M_CAP	Benign	0.0090	T
MetaRNN	Uncertain	0.46	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0060	D;D;D;D;D;D
Sift4G	Benign	0.072	T;T;T;T;T;T
Polyphen		0.70	P;P;.;P;P;P
Vest4		0.33
MutPred		0.79		Gain of ubiquitination at K103 (P = 0.1317);Gain of ubiquitination at K103 (P = 0.1317);.;Gain of ubiquitination at K103 (P = 0.1317);Gain of ubiquitination at K103 (P = 0.1317);Gain of ubiquitination at K103 (P = 0.1317);
MVP		0.39
MPC		0.32
ClinPred		0.92	D
GERP RS		3.7
Varity_R		0.87
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-208478111;