NM_001963.6:c.-382A>G

Variant names:

• chr4-109912954-A-G
• rs4444903
• NM_001963.6:c.-382A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.506
• Publications: 260 publications found

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)

ACMG classification

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76812 AN: 151930 Hom.: 20905 Cov.: 33

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.: 0 AF XY: 0.440 AC XY: 20451 AN XY: 46492

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

GnomAD4 genome AF: 0.506 AC: 76910 AN: 152048 Hom.: 20948 Cov.: 33 AF XY: 0.505 AC XY: 37518 AN XY: 74308

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

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:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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
DANN	Benign	0.75
PhyloP100		0.51
PromoterAI		0.017	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4444903; hg19: chr4-110834110;