rs11569017

Positions:

• chr4-109980955-A-T

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.2351A>T​(p.Asp784Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.06 in 1,613,974 control chromosomes in the GnomAD database, including 3,671 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (367 hom., cov: 32)
  • Exomes 𝑓: 0.061 (3304 hom.)
• Consequence: EGF NM_001963.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.62

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 (MetaRNN=0.0013268888).
• BP6: Variant 4-109980955-A-T is Benign according to our data. Variant chr4-109980955-A-T is described in ClinVar as [Benign]. Clinvar id is 347246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGF	NM_001963.6	c.2351A>T	p.Asp784Val	missense_variant	15/24	ENST00000265171.10
EGF	NM_001178130.3	c.2351A>T	p.Asp784Val	missense_variant	15/23
EGF	NM_001178131.3	c.2225A>T	p.Asp742Val	missense_variant	14/23
EGF	NM_001357021.2	c.2225A>T	p.Asp742Val	missense_variant	14/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGF	ENST00000265171.10	c.2351A>T	p.Asp784Val	missense_variant	15/24	1	NM_001963.6	P1

Frequencies

GnomAD3 genomes AF: 0.0530 AC: 8057 AN: 152082 Hom.: 367 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.0798

Gnomad ASJ AF: 0.0850

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.0711

Gnomad FIN AF: 0.0465

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0574

Gnomad OTH AF: 0.0612

GnomAD3 exomes AF: 0.0733 AC: 18423 AN: 251416 Hom.: 881 AF XY: 0.0729 AC XY: 9899 AN XY: 135870

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.0795

Gnomad EAS exome AF: 0.187

Gnomad SAS exome AF: 0.0757

Gnomad FIN exome AF: 0.0537

Gnomad NFE exome AF: 0.0572

Gnomad OTH exome AF: 0.0701

GnomAD4 exome AF: 0.0607 AC: 88719 AN: 1461774 Hom.: 3304 Cov.: 31 AF XY: 0.0612 AC XY: 44476 AN XY: 727194

Gnomad4 AFR exome AF: 0.00911

Gnomad4 AMR exome AF: 0.0985

Gnomad4 ASJ exome AF: 0.0793

Gnomad4 EAS exome AF: 0.202

Gnomad4 SAS exome AF: 0.0733

Gnomad4 FIN exome AF: 0.0565

Gnomad4 NFE exome AF: 0.0545

Gnomad4 OTH exome AF: 0.0616

GnomAD4 genome AF: 0.0530 AC: 8059 AN: 152200 Hom.: 367 Cov.: 32 AF XY: 0.0552 AC XY: 4108 AN XY: 74414

Gnomad4 AFR AF: 0.0116

Gnomad4 AMR AF: 0.0797

Gnomad4 ASJ AF: 0.0850

Gnomad4 EAS AF: 0.198

Gnomad4 SAS AF: 0.0716

Gnomad4 FIN AF: 0.0465

Gnomad4 NFE AF: 0.0574

Gnomad4 OTH AF: 0.0639

Alfa AF: 0.0624 Hom.: 292

Bravo AF: 0.0529

TwinsUK AF: 0.0553 AC: 205

ALSPAC AF: 0.0524 AC: 202

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.0597 AC: 513

ExAC AF: 0.0704 AC: 8552

Asia WGS AF: 0.110 AC: 384 AN: 3478

EpiCase AF: 0.0593

EpiControl AF: 0.0581

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	Feb 03, 2020	This variant is associated with the following publications: (PMID: 16574953) -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.94
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.83	T;T;T
MetaRNN	Benign	0.0013	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-2.4	N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.0040	B;B;.
Vest4		0.18
MPC		0.26
ClinPred		0.013	T
GERP RS		3.7
Varity_R		0.50
gMVP		0.59

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: rs11569017; hg19: chr4-110902111; COSMIC: COSV54483507; COSMIC: COSV54483507;