chr4-109912954-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001963.6(EGF):c.-382A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 241,254 control chromosomes in the GnomAD database, including 29,908 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.51 ( 20948 hom., cov: 33)

Exomes 𝑓: 0.43 ( 8960 hom. )

Consequence

EGF
NM_001963.6 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 0.506

Publications

260 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6 link	c.-382A>G	5_prime_UTR_variant	Exon 1 of 24	ENST00000265171.10	NP_001954.2	P01133-1
EGF	NM_001178130.3 link	c.-382A>G	5_prime_UTR_variant	Exon 1 of 23		NP_001171601.1	P01133-3
EGF	NM_001178131.3 link	c.-382A>G	5_prime_UTR_variant	Exon 1 of 23		NP_001171602.1	P01133-2
EGF	NM_001357021.2 link	c.-382A>G	5_prime_UTR_variant	Exon 1 of 20		NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
EGF	ENST00000265171.10 link	c.-382A>G	5_prime_UTR_variant	Exon 1 of 24	1	NM_001963.6	ENSP00000265171.5	P01133-1
EGF	ENST00000509793.5 link	c.-382A>G	5_prime_UTR_variant	Exon 1 of 23	2		ENSP00000424316.1	P01133-2
EGF	ENST00000652245.1 link	c.-382A>G	5_prime_UTR_variant	Exon 1 of 20			ENSP00000498337.1	A0A494C018

Frequencies

GnomAD3 genomes

AF:

0.506

AC:

76812

AN:

151930

Hom.:

20905

Cov.:

show subpopulations

Gnomad AFR

AF:

0.696

Gnomad AMI

AF:

0.487

Gnomad AMR

AF:

0.516

Gnomad ASJ

AF:

0.472

Gnomad EAS

AF:

0.693

Gnomad SAS

AF:

0.510

Gnomad FIN

AF:

0.352

Gnomad MID

AF:

0.503

Gnomad NFE

AF:

0.399

Gnomad OTH

AF:

0.501

GnomAD4 exome

AF:

0.433

AC:

38620

AN:

89206

Hom.:

8960

Cov.:

AF XY:

0.440

AC XY:

20451

AN XY:

46492

show subpopulations

African (AFR)

AF:

0.684

AC:

1702

AN:

2488

American (AMR)

AF:

0.536

AC:

2271

AN:

4238

Ashkenazi Jewish (ASJ)

AF:

0.461

AC:

949

AN:

2058

East Asian (EAS)

AF:

0.707

AC:

3138

AN:

4440

South Asian (SAS)

AF:

0.476

AC:

5948

AN:

12494

European-Finnish (FIN)

AF:

0.352

AC:

1515

AN:

4304

Middle Eastern (MID)

AF:

0.500

AC:

160

AN:

320

European-Non Finnish (NFE)

AF:

0.386

AC:

20955

AN:

54238

Other (OTH)

AF:

0.428

AC:

1982

AN:

4626

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

984

1968

2952

3936

4920

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.506

AC:

76910

AN:

152048

Hom.:

20948

Cov.:

AF XY:

0.505

AC XY:

37518

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.696

AC:

28862

AN:

41480

American (AMR)

AF:

0.515

AC:

7860

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.472

AC:

1640

AN:

3472

East Asian (EAS)

AF:

0.695

AC:

3591

AN:

5170

South Asian (SAS)

AF:

0.511

AC:

2460

AN:

4814

European-Finnish (FIN)

AF:

0.352

AC:

3728

AN:

10580

Middle Eastern (MID)

AF:

0.510

AC:

150

AN:

294

European-Non Finnish (NFE)

AF:

0.399

AC:

27110

AN:

67960

Other (OTH)

AF:

0.505

AC:

1066

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1805

3610

5414

7219

9024

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.443

Hom.:

63311

Bravo

AF:

0.530

Asia WGS

AF:

0.602

AC:

2097

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17851837, 19179548, 14973082, 19520791, 17175377, 22236006, 17433039, 21440548, 23403233, 22782629, 22106858, 22621366, 18167406, 20203692, 22129558, 19840254, 22829952, 11844511) -

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

Mar 06, 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. -

Cholangiocarcinoma

Other:1

Dec 10, 2022

Department of Surgery, Campus Charité Mitte Campus Virchow-klinikum, Charite-Universitaetsmedizin Berlin

Significance:other

Review Status:no assertion criteria provided

Collection Method:research

No association with disease-free or overall survival after resection of intrahepatic Cholangiocarcinoma No association with disease-free or overall survival

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

8.4

(source)

DANN

Benign

0.75

PhyloP100

0.51

PromoterAI

0.017

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

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chr4-109912954-A-G

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