chr2-42261179-C-A

Variant names:

• chr2-42261179-C-A
• NM_019063.5:c.397C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019063.5(EML4):​c.397C>A​(p.His133Asn) 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: 5.75

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24302411).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EML4	NM_019063.5	c.397C>A	p.His133Asn	missense_variant	Exon 4 of 23	ENST00000318522.10	NP_061936.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EML4	ENST00000318522.10	c.397C>A	p.His133Asn	missense_variant	Exon 4 of 23	1	NM_019063.5	ENSP00000320663.5
EML4	ENST00000402711.6	c.339-1999C>A		intron_variant	Intron 3 of 21	1		ENSP00000385059.2
EML4	ENST00000409040.1	n.628C>A		non_coding_transcript_exon_variant	Exon 4 of 4	1
EML4	ENST00000401738.3	c.397C>A	p.His133Asn	missense_variant	Exon 4 of 24	5		ENSP00000384939.3

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

Feb 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.397C>A (p.H133N) alteration is located in exon 4 (coding exon 4) of the EML4 gene. This alteration results from a C to A substitution at nucleotide position 397, causing the histidine (H) at amino acid position 133 to be replaced by an asparagine (N). 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	0.065
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.017	T;T
Eigen	Benign	0.035
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.14
Sift	Benign	0.12	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.0030	B;.
Vest4		0.59
MutPred		0.19		Loss of glycosylation at K128 (P = 0.1583);Loss of glycosylation at K128 (P = 0.1583);
MVP		0.48
MPC		0.079
ClinPred		0.60	D
GERP RS		5.5
Varity_R		0.14
gMVP		0.085

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-42488319;