4-109913381-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001963.6(EGF):c.46A>C(p.Ser16Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,613,952 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S16T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0032 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 33 hom. )

Consequence

EGF
NM_001963.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.423

Publications

11 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=0.0047091246).

BP6

Variant 4-109913381-A-C is Benign according to our data. Variant chr4-109913381-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 347224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00323 (492/152262) while in subpopulation EAS AF = 0.0257 (133/5176). AF 95% confidence interval is 0.0221. There are 7 homozygotes in GnomAd4. There are 336 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 492 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6 link	c.46A>C	p.Ser16Arg	missense_variant	Exon 1 of 24	ENST00000265171.10	NP_001954.2	P01133-1
EGF	NM_001178130.3 link	c.46A>C	p.Ser16Arg	missense_variant	Exon 1 of 23		NP_001171601.1	P01133-3
EGF	NM_001178131.3 link	c.46A>C	p.Ser16Arg	missense_variant	Exon 1 of 23		NP_001171602.1	P01133-2
EGF	NM_001357021.2 link	c.46A>C	p.Ser16Arg	missense_variant	Exon 1 of 20		NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EGF	ENST00000265171.10 link	c.46A>C	p.Ser16Arg	missense_variant	Exon 1 of 24	1	NM_001963.6	ENSP00000265171.5	P01133-1
EGF	ENST00000503392.1 link	c.46A>C	p.Ser16Arg	missense_variant	Exon 1 of 23	1		ENSP00000421384.1	P01133-3
EGF	ENST00000509793.5 link	c.46A>C	p.Ser16Arg	missense_variant	Exon 1 of 23	2		ENSP00000424316.1	P01133-2
EGF	ENST00000652245.1 link	c.46A>C	p.Ser16Arg	missense_variant	Exon 1 of 20			ENSP00000498337.1	A0A494C018

Frequencies

GnomAD3 genomes

AF:

0.00323

AC:

491

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0254

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0276

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00450

AC:

1131

AN:

251146

AF XY:

0.00430

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.0264

Gnomad FIN exome

AF:

0.0250

Gnomad NFE exome

AF:

0.000555

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00178

AC:

2606

AN:

1461690

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

1226

AN XY:

727150

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33470

American (AMR)

AF:

0.0000448

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.000459

AC:

AN:

26136

East Asian (EAS)

AF:

0.0277

AC:

1098

AN:

39692

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0230

AC:

1229

AN:

53410

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000138

AC:

153

AN:

1111894

Other (OTH)

AF:

0.00164

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

149

298

447

596

745

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00323

AC:

492

AN:

152262

Hom.:

Cov.:

AF XY:

0.00451

AC XY:

336

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41560

American (AMR)

AF:

0.000131

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.0257

AC:

133

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0276

AC:

293

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000720

AC:

AN:

68024

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00103

Hom.:

Bravo

AF:

0.00125

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00404

AC:

490

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 04, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EGF: BP4, BS1, BS2 -

Renal hypomagnesemia 4

Benign:1

Jan 12, 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

Uncertain

0.41

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.22

CADD

Benign

6.2

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.48

.;T;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.79

T;T;T

MetaRNN

Benign

0.0047

T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Uncertain

2.1

M;M;M

PhyloP100

0.42

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.9

N;N;N

REVEL

Uncertain

0.40

Sift

Uncertain

0.015

D;D;D

Sift4G

Benign

0.061

T;T;T

Polyphen

0.96

D;P;.

Vest4

0.23

MutPred

0.57

Loss of ubiquitination at K14 (P = 0.0524);Loss of ubiquitination at K14 (P = 0.0524);Loss of ubiquitination at K14 (P = 0.0524);

MVP

0.86

MPC

0.58

ClinPred

0.018

GERP RS

-5.5

PromoterAI

0.17

Neutral

(source)

Varity_R

0.12

gMVP

0.48

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

4-109913381-A-C

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