2-42256546-A-T

Variant names:

• chr2-42256546-A-T
• rs151065528
• NM_019063.5:c.254A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_019063.5(EML4):​c.254A>T​(p.Asn85Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,560 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N85S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EML4 NM_019063.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.79
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019063.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EML4	NM_019063.5	MANE Select	c.254A>T	p.Asn85Ile	missense	Exon 3 of 23	NP_061936.3
	EML4	NM_001410776.1		c.254A>T	p.Asn85Ile	missense	Exon 3 of 24	NP_001397705.1	B5MBZ0
	EML4	NM_001145076.3		c.254A>T	p.Asn85Ile	missense	Exon 3 of 22	NP_001138548.2	Q9HC35-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EML4	ENST00000318522.10	TSL:1 MANE Select	c.254A>T	p.Asn85Ile	missense	Exon 3 of 23	ENSP00000320663.5	Q9HC35-1
	EML4	ENST00000402711.6	TSL:1	c.254A>T	p.Asn85Ile	missense	Exon 3 of 22	ENSP00000385059.2	Q9HC35-2
	EML4	ENST00000409040.1	TSL:1	n.485A>T		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461560 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727078

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111798

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.8
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.044	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.18		Gain of MoRF binding (P = 0.109)
MVP		0.98
MPC		0.32
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.37
gMVP		0.33
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs151065528; hg19: chr2-42483686;