chr2-42256546-A-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_019063.5(EML4):​c.254A>G​(p.Asn85Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000124 in 1,613,858 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (6 hom.)
• Consequence: EML4 NM_019063.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1736067).
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

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>G	p.Asn85Ser	missense	Exon 3 of 23	NP_061936.3
	EML4	NM_001410776.1		c.254A>G	p.Asn85Ser	missense	Exon 3 of 24	NP_001397705.1	B5MBZ0
	EML4	NM_001145076.3		c.254A>G	p.Asn85Ser	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>G	p.Asn85Ser	missense	Exon 3 of 23	ENSP00000320663.5	Q9HC35-1
	EML4	ENST00000402711.6	TSL:1	c.254A>G	p.Asn85Ser	missense	Exon 3 of 22	ENSP00000385059.2	Q9HC35-2
	EML4	ENST00000409040.1	TSL:1	n.485A>G		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000279 AC: 70 AN: 251322 AF XY: 0.000317

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000126 AC: 184 AN: 1461558 Hom.: 6 Cov.: 30 AF XY: 0.000187 AC XY: 136 AN XY: 727078

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

American (AMR) AF: 0.000715 AC: 32 AN: 44724

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

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39678

South Asian (SAS) AF: 0.00119 AC: 103 AN: 86226

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

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111798

Other (OTH) AF: 0.0000994 AC: 6 AN: 60378

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74470

African (AFR) AF: 0.00 AC: 0 AN: 41560

American (AMR) AF: 0.000523 AC: 8 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.0000548

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T
Eigen	Benign	0.042
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.17	T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.8
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.28
Sift	Benign	0.13	T
Sift4G	Benign	0.081	T
Polyphen		1.0	D
Vest4		0.64
MVP		0.92
MPC		0.052
ClinPred		0.10	T
GERP RS		4.5
Varity_R		0.15
gMVP		0.14
Mutation Taster		=95/5	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;