3-184257656-T-C

Position:

• chr3-184257656-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032331.4(EEF1AKMT4):​c.380T>C​(p.Val127Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00253 in 1,614,206 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (39 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (44 hom.)
• Consequence: EEF1AKMT4 NM_032331.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.10

Genes affected

EEF1AKMT4 (HGNC:53611): (EEF1A lysine methyltransferase 4) This gene encodes a member of the lysine-specific methyltransferase (KMT) family. The encoded enzyme catalyzes the methylation of lysine-36 of the eukaryotic translation elongation factor 1 alpha. Methylation by this enzyme may affect endoplasmic reticulum-related processes. [provided by RefSeq, Jul 2017]

EEF1AKMT4-ECE2 (HGNC:53615): (EEF1AKMT4-ECE2 readthrough) This gene represents naturally occurring readthrough transcription between adjacent genes eukaryotic translation elongation factor 1 alpha lysine methyltransferase 4 (GeneID: 110599564) and endothelin converting enzyme 2 (GeneID:9718). The readthrough transcript representing this gene encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009235114).
• BP6: Variant 3-184257656-T-C is Benign according to our data. Variant chr3-184257656-T-C is described in ClinVar as [Benign]. Clinvar id is 789726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0124 (1893/152354) while in subpopulation AFR AF= 0.0417 (1736/41582). AF 95% confidence interval is 0.0401. There are 39 homozygotes in gnomad4. There are 920 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 39 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EEF1AKMT4	NM_032331.4	c.380T>C	p.Val127Ala	missense_variant	2/3	ENST00000324557.9	NP_115707.2
EEF1AKMT4-ECE2	NM_014693.4	c.380T>C	p.Val127Ala	missense_variant	2/19		NP_055508.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EEF1AKMT4	ENST00000324557.9	c.380T>C	p.Val127Ala	missense_variant	2/3	1	NM_032331.4	ENSP00000314295.5
EEF1AKMT4-ECE2	ENST00000402825.7	c.380T>C	p.Val127Ala	missense_variant	2/19	1		ENSP00000384223.3

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1893 AN: 152236 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00345 AC: 866 AN: 251378 Hom.: 15 AF XY: 0.00263 AC XY: 358 AN XY: 135900

Gnomad AFR exome AF: 0.0426

Gnomad AMR exome AF: 0.00353

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000281

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00150 AC: 2198 AN: 1461852 Hom.: 44 Cov.: 34 AF XY: 0.00134 AC XY: 973 AN XY: 727224

Gnomad4 AFR exome AF: 0.0459

Gnomad4 AMR exome AF: 0.00329

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.000210

Gnomad4 OTH exome AF: 0.00382

GnomAD4 genome AF: 0.0124 AC: 1893 AN: 152354 Hom.: 39 Cov.: 33 AF XY: 0.0123 AC XY: 920 AN XY: 74506

Gnomad4 AFR AF: 0.0417

Gnomad4 AMR AF: 0.00680

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00319 Hom.: 10

Bravo AF: 0.0146

ESP6500AA AF: 0.0433 AC: 191

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00387 AC: 470

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D;T
MetaRNN	Benign	0.0092	T;T
MetaSVM	Benign	-0.44	T
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.7	D;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.14	T;T
Vest4		0.79
MVP		0.84
MPC		0.83
ClinPred		0.030	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.18
gMVP		0.60

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: rs74351089; hg19: chr3-183975444;