Variant 2-42261255-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000318522.10(EML4):c.473G>A(p.Arg158Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,572 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: 0.0000068 ( 0 hom. )

Consequence

EML4
ENST00000318522.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.56

Variant links:

Genes affected

EML4 (HGNC:1316): (EMAP like 4) This gene is a member of the echinoderm microtubule associated protein-like family. The encoded WD-repeat protein may be involved in microtubule formation. Abnormal fusion of parts of this gene with portions of the anaplastic lymphoma receptor tyrosine kinase gene, which generates EML4-ALK fusion transcripts, is one of the primary mutations associated with non-small cell lung cancer. Alternative splicing of this gene results in two transcript variants. [provided by RefSeq, Jan 2015]

EML4 links:

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ACMG classification

Classification made for transcript

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	Protein	UniProt
EML4	NM_019063.5 linkuse as main transcript	c.473G>A	p.Arg158Lys	missense_variant	4/23	ENST00000318522.10	NP_061936.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EML4	ENST00000318522.10 linkuse as main transcript	c.473G>A	p.Arg158Lys	missense_variant	4/23	1	NM_019063.5	ENSP00000320663	P3	Q9HC35-1
EML4	ENST00000402711.6 linkuse as main transcript	c.339-1923G>A		intron_variant		1		ENSP00000385059		Q9HC35-2
EML4	ENST00000409040.1 linkuse as main transcript	n.704G>A		non_coding_transcript_exon_variant	4/4	1
EML4	ENST00000401738.3 linkuse as main transcript	c.473G>A	p.Arg158Lys	missense_variant	4/24	5		ENSP00000384939	A1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251314

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461572

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

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

Mar 17, 2023

The c.473G>A (p.R158K) alteration is located in exon 4 (coding exon 4) of the EML4 gene. This alteration results from a G to A substitution at nucleotide position 473, causing the arginine (R) at amino acid position 158 to be replaced by a lysine (K). 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

0.10

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.016

T;T

Eigen

Benign

-0.076

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.042

MetaRNN

Benign

0.25

T;T

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

1.9

L;.

MutationTaster

Benign

0.95

D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.80

N;N

REVEL

Uncertain

0.39

Sift

Benign

0.10

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.52

P;.

Vest4

0.57

MutPred

0.36

Gain of ubiquitination at R158 (P = 9e-04);Gain of ubiquitination at R158 (P = 9e-04);

MVP

0.89

MPC

0.048

ClinPred

0.17

GERP RS

4.6

Varity_R

0.19

gMVP

0.048

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.31

Position offset: 39

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