4-109912954-A-G

Position:

• chr4-109912954-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_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. Variant has been reported in ClinVar as Benign (★★).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 4-109912954-A-G is Benign according to our data. Variant chr4-109912954-A-G is described in ClinVar as [Benign]. Clinvar id is 225998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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/exons	MANE	UniProt
EGF	NM_001963.6	c.-382A>G		5_prime_UTR_variant	1/24	ENST00000265171.10
EGF	NM_001178130.3	c.-382A>G		5_prime_UTR_variant	1/23
EGF	NM_001178131.3	c.-382A>G		5_prime_UTR_variant	1/23
EGF	NM_001357021.2	c.-382A>G		5_prime_UTR_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGF	ENST00000265171.10	c.-382A>G		5_prime_UTR_variant	1/24	1	NM_001963.6	P1
EGF	ENST00000509793.5	c.-382A>G		5_prime_UTR_variant	1/23	2
EGF	ENST00000652245.1	c.-382A>G		5_prime_UTR_variant	1/20

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

Gnomad4 AFR exome AF: 0.684

Gnomad4 AMR exome AF: 0.536

Gnomad4 ASJ exome AF: 0.461

Gnomad4 EAS exome AF: 0.707

Gnomad4 SAS exome AF: 0.476

Gnomad4 FIN exome AF: 0.352

Gnomad4 NFE exome AF: 0.386

Gnomad4 OTH exome AF: 0.428

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

Gnomad4 AFR AF: 0.696

Gnomad4 AMR AF: 0.515

Gnomad4 ASJ AF: 0.472

Gnomad4 EAS AF: 0.695

Gnomad4 SAS AF: 0.511

Gnomad4 FIN AF: 0.352

Gnomad4 NFE AF: 0.399

Gnomad4 OTH AF: 0.505

Alfa AF: 0.425 Hom.: 22543

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	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) -

Renal hypomagnesemia 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

Cholangiocarcinoma Other:1

other, no assertion criteria provided

research

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

Dec 10, 2022

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

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

LitVar

Other links and lift over

dbSNP: rs4444903; hg19: chr4-110834110;