rs11568993

chr4-109976159-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001963.6(EGF):c.1977C>T(p.Cys659=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0714 in 1,614,006 control chromosomes in the GnomAD database, including 4,842 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (334 hom., cov: 33)
  • Exomes 𝑓: 0.073 (4508 hom.)
• Consequence: EGF NM_001963.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.24

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 4-109976159-C-T is Benign according to our data. Variant chr4-109976159-C-T is described in ClinVar as [Benign]. Clinvar id is 347241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-109976159-C-T is described in Lovd as [Benign]. Variant chr4-109976159-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGF	NM_001963.6	c.1977C>T	p.Cys659=	synonymous_variant	13/24	ENST00000265171.10
EGF	NM_001178130.3	c.1977C>T	p.Cys659=	synonymous_variant	13/23
EGF	NM_001178131.3	c.1851C>T	p.Cys617=	synonymous_variant	12/23
EGF	NM_001357021.2	c.1851C>T	p.Cys617=	synonymous_variant	12/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGF	ENST00000265171.10	c.1977C>T	p.Cys659=	synonymous_variant	13/24	1	NM_001963.6	P1

Frequencies

GnomAD3 genomes AF: 0.0528 AC: 8035 AN: 152132 Hom.: 333 Cov.: 33

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0536

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0158

Gnomad FIN AF: 0.0610

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0776

Gnomad OTH AF: 0.0630

GnomAD3 exomes AF: 0.0563 AC: 14140 AN: 251270 Hom.: 569 AF XY: 0.0569 AC XY: 7731 AN XY: 135792

Gnomad AFR exome AF: 0.0116

Gnomad AMR exome AF: 0.0454

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0191

Gnomad FIN exome AF: 0.0566

Gnomad NFE exome AF: 0.0772

Gnomad OTH exome AF: 0.0727

GnomAD4 exome AF: 0.0734 AC: 107267 AN: 1461756 Hom.: 4508 Cov.: 32 AF XY: 0.0717 AC XY: 52116 AN XY: 727182

Gnomad4 AFR exome AF: 0.0123

Gnomad4 AMR exome AF: 0.0470

Gnomad4 ASJ exome AF: 0.135

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0194

Gnomad4 FIN exome AF: 0.0576

Gnomad4 NFE exome AF: 0.0823

Gnomad4 OTH exome AF: 0.0734

GnomAD4 genome AF: 0.0528 AC: 8032 AN: 152250 Hom.: 334 Cov.: 33 AF XY: 0.0507 AC XY: 3773 AN XY: 74438

Gnomad4 AFR AF: 0.0134

Gnomad4 AMR AF: 0.0535

Gnomad4 ASJ AF: 0.134

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0160

Gnomad4 FIN AF: 0.0610

Gnomad4 NFE AF: 0.0775

Gnomad4 OTH AF: 0.0624

Alfa AF: 0.0759 Hom.: 829

Bravo AF: 0.0533

Asia WGS AF: 0.0140 AC: 51 AN: 3478

EpiCase AF: 0.0872

EpiControl AF: 0.0875

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2019	- -

Renal hypomagnesemia 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	5.5
Dann	Benign	0.51

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: rs11568993; hg19: chr4-110897315; COSMIC: COSV54480122; COSMIC: COSV54480122;