Genetic Variant EN1:p.Ala201Ala (chr2-118846565-C-G) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_001426.4(EN1):c.603G>C(p.Ala201Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00529 in 1,209,590 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0040 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0055 ( 20 hom. )

Consequence

EN1
NM_001426.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.290

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 2-118846565-C-G is Benign according to our data. Variant chr2-118846565-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3388064.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.29 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EN1	NM_001426.4 link	c.603G>C	p.Ala201Ala	synonymous_variant	Exon 1 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.603G>C	p.Ala201Ala	synonymous_variant	Exon 1 of 2	2	NM_001426.4	ENSP00000295206.5		Q05925

Frequencies

GnomAD3 genomes

AF:

0.00404

AC:

601

AN:

148898

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00107

Gnomad AMI

AF:

0.0507

Gnomad AMR

AF:

0.00781

Gnomad ASJ

AF:

0.00555

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000320

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00536

Gnomad OTH

AF:

0.00587

GnomAD3 exomes

AF:

0.00569

AC:

AN:

2814

Hom.:

AF XY:

0.00764

AC XY:

AN XY:

1570

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0167

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:

0.00888

Gnomad OTH exome

AF:

0.0147

GnomAD4 exome

AF:

0.00547

AC:

5797

AN:

1060584

Hom.:

Cov.:

AF XY:

0.00542

AC XY:

2727

AN XY:

503452

show subpopulations

Gnomad4 AFR exome

AF:

0.000413

Gnomad4 AMR exome

AF:

0.00680

Gnomad4 ASJ exome

AF:

0.00692

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000769

Gnomad4 FIN exome

AF:

0.00105

Gnomad4 NFE exome

AF:

0.00592

Gnomad4 OTH exome

AF:

0.00547

GnomAD4 genome

AF:

0.00403

AC:

601

AN:

149006

Hom.:

Cov.:

AF XY:

0.00369

AC XY:

268

AN XY:

72712

show subpopulations

Gnomad4 AFR

AF:

0.00107

Gnomad4 AMR

AF:

0.00780

Gnomad4 ASJ

AF:

0.00555

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.000320

Gnomad4 NFE

AF:

0.00536

Gnomad4 OTH

AF:

0.00581

Alfa

AF:

0.000853

Hom.:

Bravo

AF:

0.00431

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EN1: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

9.9

DANN

Benign

0.81

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