4-109993271-A-T

Position:

chr4-109993271-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000265171.10(EGF):c.2759A>T(p.Glu920Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.814 in 1,613,468 control chromosomes in the GnomAD database, including 537,711 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. E920E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.86 ( 56818 hom., cov: 29)

Exomes 𝑓: 0.81 ( 480893 hom. )

Consequence

EGF
ENST00000265171.10 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.39

Variant links:

Genes affected

EGF (HGNC:3229): (epidermal growth factor) This gene encodes a member of the epidermal growth factor superfamily. The encoded preproprotein is proteolytically processed to generate the 53-amino acid epidermal growth factor peptide. This protein acts a potent mitogenic factor that plays an important role in the growth, proliferation and differentiation of numerous cell types. This protein acts by binding with high affinity to the cell surface receptor, epidermal growth factor receptor. Defects in this gene are the cause of hypomagnesemia type 4. Dysregulation of this gene has been associated with the growth and progression of certain cancers. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

EGF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.787117E-7).

BP6

Variant 4-109993271-A-T is Benign according to our data. Variant chr4-109993271-A-T is described in ClinVar as [Benign]. Clinvar id is 347252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-109993271-A-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EGF	NM_001963.6 linkuse as main transcript	c.2759A>T	p.Glu920Val	missense_variant	19/24	ENST00000265171.10	NP_001954.2
EGF	NM_001178131.3 linkuse as main transcript	c.2633A>T	p.Glu878Val	missense_variant	18/23		NP_001171602.1
EGF	NM_001357021.2 linkuse as main transcript	c.2390A>T	p.Glu797Val	missense_variant	16/20		NP_001343950.1
EGF	NM_001178130.3 linkuse as main transcript	c.2735-1462A>T		intron_variant			NP_001171601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10 linkuse as main transcript	c.2759A>T	p.Glu920Val	missense_variant	19/24	1	NM_001963.6	ENSP00000265171	P1	P01133-1

Frequencies

GnomAD3 genomes

AF:

0.861

AC:

130720

AN:

151852

Hom.:

56754

Cov.:

show subpopulations

Gnomad AFR

AF:

0.964

Gnomad AMI

AF:

0.711

Gnomad AMR

AF:

0.901

Gnomad ASJ

AF:

0.858

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.865

Gnomad FIN

AF:

0.795

Gnomad MID

AF:

0.831

Gnomad NFE

AF:

0.791

Gnomad OTH

AF:

0.863

GnomAD3 exomes

AF:

0.846

AC:

212717

AN:

251336

Hom.:

90871

AF XY:

0.839

AC XY:

113987

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.968

Gnomad AMR exome

AF:

0.932

Gnomad ASJ exome

AF:

0.848

Gnomad EAS exome

AF:

0.999

Gnomad SAS exome

AF:

0.859

Gnomad FIN exome

AF:

0.798

Gnomad NFE exome

AF:

0.784

Gnomad OTH exome

AF:

0.840

GnomAD4 exome

AF:

0.809

AC:

1182977

AN:

1461498

Hom.:

480893

Cov.:

AF XY:

0.809

AC XY:

588573

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.970

Gnomad4 AMR exome

AF:

0.927

Gnomad4 ASJ exome

AF:

0.847

Gnomad4 EAS exome

AF:

0.999

Gnomad4 SAS exome

AF:

0.856

Gnomad4 FIN exome

AF:

0.796

Gnomad4 NFE exome

AF:

0.788

Gnomad4 OTH exome

AF:

0.836

GnomAD4 genome

AF:

0.861

AC:

130845

AN:

151970

Hom.:

56818

Cov.:

AF XY:

0.863

AC XY:

64083

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.964

Gnomad4 AMR

AF:

0.901

Gnomad4 ASJ

AF:

0.858

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.864

Gnomad4 FIN

AF:

0.795

Gnomad4 NFE

AF:

0.791

Gnomad4 OTH

AF:

0.865

Alfa

AF:

0.810

Hom.:

37428

Bravo

AF:

0.874

TwinsUK

AF:

0.796

AC:

2952

ALSPAC

AF:

0.795

AC:

3065

ESP6500AA

AF:

0.964

AC:

4246

ESP6500EA

AF:

0.790

AC:

6795

ExAC

AF:

0.841

AC:

102064

Asia WGS

AF:

0.946

AC:

3291

AN:

3478

EpiCase

AF:

0.794

EpiControl

AF:

0.798

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Renal hypomagnesemia 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.17

DANN

Benign

0.79

DEOGEN2

Benign

0.38

.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0032

LIST_S2

Benign

0.29

T;T

MetaRNN

Benign

8.8e-7

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.90

.;L

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.23

PROVEAN

Benign

1.8

N;N

REVEL

Benign

0.069

Sift

Benign

1.0

T;T

Sift4G

Benign

0.81

T;T

Polyphen

0.0

B;B

Vest4

0.059

MPC

0.21

ClinPred

0.00038

GERP RS

1.3

Varity_R

0.089

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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