2-42280936-A-C

Position:

• chr2-42280936-A-C

Variant summary

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

The NM_019063.5(EML4):​c.754A>C​(p.Thr252Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: EML4 NM_019063.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.22

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]

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=0.36873037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EML4	NM_019063.5	c.754A>C	p.Thr252Pro	missense_variant	7/23	ENST00000318522.10	NP_061936.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EML4	ENST00000318522.10	c.754A>C	p.Thr252Pro	missense_variant	7/23	1	NM_019063.5	ENSP00000320663	P3
EML4	ENST00000402711.6	c.580A>C	p.Thr194Pro	missense_variant	6/22	1		ENSP00000385059
EML4	ENST00000401738.3	c.787A>C	p.Thr263Pro	missense_variant	8/24	5		ENSP00000384939	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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

Sep 20, 2023

The c.754A>C (p.T252P) alteration is located in exon 7 (coding exon 7) of the EML4 gene. This alteration results from a A to C substitution at nucleotide position 754, causing the threonine (T) at amino acid position 252 to be replaced by a proline (P). 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	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.;T
Eigen	Benign	-0.087
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.090	N;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.5	D;N;D
REVEL	Benign	0.28
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.91	P;.;.
Vest4		0.63
MutPred		0.40		Gain of catalytic residue at T252 (P = 0.0194);.;.;
MVP		0.53
MPC		0.061
ClinPred		0.90	D
GERP RS		4.1
Varity_R		0.53
gMVP		0.41

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: chr2-42508076;