12-57780260-G-C

Position:

• chr12-57780260-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015433.3(EEF1AKMT3):​c.295G>C​(p.Asp99His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EEF1AKMT3 NM_015433.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.446

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04715261).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EEF1AKMT3	NM_015433.3	c.295G>C	p.Asp99His	missense_variant	3/3	ENST00000300209.13	NP_056248.2
EEF1AKMT3	NM_206914.2	c.434G>C	p.Gly145Ala	missense_variant	4/4		NP_996797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EEF1AKMT3	ENST00000300209.13	c.295G>C	p.Asp99His	missense_variant	3/3	1	NM_015433.3	ENSP00000300209	P1
EEF1AKMT3	ENST00000333012.5	c.434G>C	p.Gly145Ala	missense_variant	4/4	1		ENSP00000327425
EEF1AKMT3	ENST00000548256.5	c.308G>C	p.Gly103Ala	missense_variant	4/4	4		ENSP00000447718
EEF1AKMT3	ENST00000551420.1	c.-249G>C		5_prime_UTR_variant	3/3	2		ENSP00000448163

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

May 30, 2024

The c.295G>C (p.D99H) alteration is located in exon 3 (coding exon 3) of the METTL21B gene. This alteration results from a G to C substitution at nucleotide position 295, causing the aspartic acid (D) at amino acid position 99 to be replaced by a histidine (H). 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	Benign	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.74
DEOGEN2	Benign	0.00064	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.89	D;D;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.030
Sift	Benign	1.0	T
Sift4G	Benign	0.41	T
Polyphen		0.0020	B
Vest4		0.11
MutPred		0.39		Loss of helix (P = 0.1299);
MVP		0.35
MPC		0.80
ClinPred		0.060	T
GERP RS		3.2
Varity_R		0.20
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-58174043;