chr4-109993271-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001963.6(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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in 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
NM_001963.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.39

Publications

62 publications found

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 Gene-Disease associations (from GenCC):

familial primary hypomagnesemia with normocalciuria and normocalcemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
renal hypomagnesemia 4
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

EGF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 347252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
EGF	NM_001963.6 link	c.2759A>T	p.Glu920Val	missense_variant	Exon 19 of 24	ENST00000265171.10	NP_001954.2	P01133-1
EGF	NM_001178131.3 link	c.2633A>T	p.Glu878Val	missense_variant	Exon 18 of 23		NP_001171602.1	P01133-2
EGF	NM_001357021.2 link	c.2390A>T	p.Glu797Val	missense_variant	Exon 16 of 20		NP_001343950.1
EGF	NM_001178130.3 link	c.2735-1462A>T		intron_variant	Intron 18 of 22		NP_001171601.1	P01133-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10 link	c.2759A>T	p.Glu920Val	missense_variant	Exon 19 of 24	1	NM_001963.6	ENSP00000265171.5		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

GnomAD2 exomes

AF:

0.846

AC:

212717

AN:

251336

AF XY:

0.839

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 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

African (AFR)

AF:

0.970

AC:

32472

AN:

33466

American (AMR)

AF:

0.927

AC:

41449

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.847

AC:

22140

AN:

26132

East Asian (EAS)

AF:

0.999

AC:

39676

AN:

39696

South Asian (SAS)

AF:

0.856

AC:

73871

AN:

86248

European-Finnish (FIN)

AF:

0.796

AC:

42493

AN:

53394

Middle Eastern (MID)

AF:

0.831

AC:

4696

AN:

5650

European-Non Finnish (NFE)

AF:

0.788

AC:

875714

AN:

1111822

Other (OTH)

AF:

0.836

AC:

50466

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

12648

25295

37943

50590

63238

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20756

41512

62268

83024

103780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.861

AC:

130845

AN:

151970

Hom.:

56818

Cov.:

AF XY:

0.863

AC XY:

64083

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.964

AC:

39989

AN:

41496

American (AMR)

AF:

0.901

AC:

13744

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.858

AC:

2977

AN:

3470

East Asian (EAS)

AF:

1.00

AC:

5148

AN:

5150

South Asian (SAS)

AF:

0.864

AC:

4144

AN:

4796

European-Finnish (FIN)

AF:

0.795

AC:

8383

AN:

10550

Middle Eastern (MID)

AF:

0.825

AC:

241

AN:

292

European-Non Finnish (NFE)

AF:

0.791

AC:

53748

AN:

67944

Other (OTH)

AF:

0.865

AC:

1824

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

897

1793

2690

3586

4483

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

884

1768

2652

3536

4420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Renal hypomagnesemia 4

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

-1.4

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

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over