rs4698803

Positions:

• chr4-109993271-A-G
• chr4-109993271-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000265171.10(EGF):​c.2759A>G​(p.Glu920Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E920V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 29)
• Consequence: EGF ENST00000265171.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.39

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.083471775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGF	NM_001963.6	c.2759A>G	p.Glu920Gly	missense_variant	19/24	ENST00000265171.10	NP_001954.2
EGF	NM_001178131.3	c.2633A>G	p.Glu878Gly	missense_variant	18/23		NP_001171602.1
EGF	NM_001357021.2	c.2390A>G	p.Glu797Gly	missense_variant	16/20		NP_001343950.1
EGF	NM_001178130.3	c.2735-1462A>G		intron_variant			NP_001171601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10	c.2759A>G	p.Glu920Gly	missense_variant	19/24	1	NM_001963.6	ENSP00000265171	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 59

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	4.4
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.083	T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.79	.;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.59	N;N
REVEL	Benign	0.082
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.19	T;T
Polyphen		0.0	B;B
Vest4		0.061
MutPred		0.39		.;Loss of glycosylation at S922 (P = 0.0453);
MVP		0.67
MPC		0.21
ClinPred		0.073	T
GERP RS		1.3
Varity_R		0.089
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs4698803; hg19: chr4-110914427;