12-57772830-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015433.3(EEF1AKMT3):c.106T>C(p.Cys36Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EEF1AKMT3 NM_015433.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.82

Genes affected

EEF1AKMT3 (HGNC:24936): (EEF1A lysine methyltransferase 3) Enables heat shock protein binding activity and protein-lysine N-methyltransferase activity. Involved in peptidyl-lysine methylation. Located in several cellular components, including centrosome; chromosome; and nucleoplasm. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29096085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EEF1AKMT3	NM_015433.3	c.106T>C	p.Cys36Arg	missense_variant	1/3	ENST00000300209.13
EEF1AKMT3	NM_206914.2	c.106T>C	p.Cys36Arg	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EEF1AKMT3	ENST00000300209.13	c.106T>C	p.Cys36Arg	missense_variant	1/3	1	NM_015433.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251232 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

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: 0.00000137 AC: 2 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727234

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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 06, 2024

The c.106T>C (p.C36R) alteration is located in exon 1 (coding exon 1) of the METTL21B gene. This alteration results from a T to C substitution at nucleotide position 106, causing the cysteine (C) at amino acid position 36 to be replaced by an arginine (R). 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	0.46
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.085	T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Benign	0.24
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		0.92	P;D
Vest4		0.18
MutPred		0.57		Gain of disorder (P = 0.0516);Gain of disorder (P = 0.0516);
MVP		0.38
MPC		2.2
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.93
gMVP		0.73

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: rs1334424639; hg19: chr12-58166613;