Genetic Variant EN1:p.Arg317Lys (chr2-118843167-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001426.4(EN1):c.950G>A(p.Arg317Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000447 in 1,608,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

EN1
NM_001426.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.16

Variant links:

Genes affected

EN1 (HGNC:3342): (engrailed homeobox 1) Homeobox-containing genes are thought to have a role in controlling development. In Drosophila, the 'engrailed' (en) gene plays an important role during development in segmentation, where it is required for the formation of posterior compartments. Different mutations in the mouse homologs, En1 and En2, produced different developmental defects that frequently are lethal. The human engrailed homologs 1 and 2 encode homeodomain-containing proteins and have been implicated in the control of pattern formation during development of the central nervous system. [provided by RefSeq, Jul 2008]

EN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.27648544).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EN1	NM_001426.4 link	c.950G>A	p.Arg317Lys	missense_variant	Exon 2 of 2	ENST00000295206.7	NP_001417.3	Q05925

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EN1	ENST00000295206.7 link	c.950G>A	p.Arg317Lys	missense_variant	Exon 2 of 2	2	NM_001426.4	ENSP00000295206.5		Q05925
EN1	ENST00000546667.1 link	n.*68G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000880

AC:

AN:

238732

Hom.:

AF XY:

0.0000850

AC XY:

AN XY:

129466

show subpopulations

Gnomad AFR exome

AF:

0.000799

Gnomad AMR exome

AF:

0.000210

Gnomad ASJ exome

AF:

0.000102

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000933

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000254

AC:

AN:

1456748

Hom.:

Cov.:

AF XY:

0.0000262

AC XY:

AN XY:

724226

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.000296

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.000230

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.000843

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000127

Hom.:

Bravo

AF:

0.000310

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.950G>A (p.R317K) alteration is located in exon 2 (coding exon 2) of the EN1 gene. This alteration results from a G to A substitution at nucleotide position 950, causing the arginine (R) at amino acid position 317 to be replaced by a lysine (K). 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

Pathogenic

0.91

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.28

MetaSVM

Pathogenic

0.82

MutationAssessor

Benign

1.1

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0090

Sift4G

Pathogenic

0.0

Polyphen

0.64

Vest4

0.56

MVP

0.89

ClinPred

0.16

GERP RS

4.7

Varity_R

0.80

gMVP

0.91

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