NM_004434.3:c.139A>C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_004434.3(EML1):c.139A>C(p.Met47Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000499 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

EML1
NM_004434.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.66

Variant links:

Genes affected

EML1 (HGNC:3330): (EMAP like 1) Human echinoderm microtubule-associated protein-like is a strong candidate for the Usher syndrome type 1A gene. Usher syndromes (USHs) are a group of genetic disorders consisting of congenital deafness, retinitis pigmentosa, and vestibular dysfunction of variable onset and severity depending on the genetic type. The disease process in USHs involves the entire brain and is not limited to the posterior fossa or auditory and visual systems. The USHs are catagorized as type I (USH1A, USH1B, USH1C, USH1D, USH1E and USH1F), type II (USH2A and USH2B) and type III (USH3). The type I is the most severe form. Gene loci responsible for these three types are all mapped. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

EML1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11052674).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000499 (73/1461892) while in subpopulation NFE AF= 0.000062 (69/1112010). AF 95% confidence interval is 0.0000499. There are 0 homozygotes in gnomad4_exome. There are 32 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EML1	NM_004434.3 link	c.139A>C	p.Met47Leu	missense_variant	Exon 2 of 22	ENST00000262233.11	NP_004425.2	O00423-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EML1	ENST00000262233.11 link	c.139A>C	p.Met47Leu	missense_variant	Exon 2 of 22	1	NM_004434.3	ENSP00000262233.7		O00423-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251488

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000499

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

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:

0.0000620

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000843

Hom.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Dec 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.139A>C (p.M47L) alteration is located in exon 2 (coding exon 2) of the EML1 gene. This alteration results from a A to C substitution at nucleotide position 139, causing the methionine (M) at amino acid position 47 to be replaced by a leucine (L). 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

0.082

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.011

T;T;T;T;.;.;T;.;T;T;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.80

T;D;T;T;T;T;T;T;T;T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.11

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.63

.;.;.;.;.;.;N;N;.;.;.

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.57

N;N;N;N;.;N;N;N;N;N;N

REVEL

Benign

0.073

Sift

Benign

1.0

T;T;T;T;.;T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;.;T;T;T;T;T;T

Polyphen

0.0, 0.0010

.;.;B;.;.;.;B;B;.;.;.

Vest4

0.46, 0.43, 0.43

MutPred

0.23

.;.;.;.;.;.;Gain of catalytic residue at M47 (P = 0.0722);Gain of catalytic residue at M47 (P = 0.0722);.;.;.;

MVP

0.19

MPC

0.52

ClinPred

0.18

GERP RS

3.0

Varity_R

0.15

gMVP

0.094

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

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