4-109993271-AG-TA

Variant names:

• chr4-109993271-AG-TA
• NM_001963.6:c.2759_2760delAGinsTA
• EGF p.Glu920Val

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001963.6(EGF):​c.2759_2760delAGinsTA​(p.Glu920Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.000173 in 49 alleles, including 0 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. E920E) has been classified as Likely benign.

• Frequency: GnomAD MNV: 𝑓 0.00017 Genomes: not found (cov: 29)
• Consequence: EGF NM_001963.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.798
• Publications: 0 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, AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001963.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGF	NM_001963.6	MANE Select	c.2759_2760delAGinsTA	p.Glu920Val	missense	N/A	NP_001954.2	P01133-1
	EGF	NM_001178131.3		c.2633_2634delAGinsTA	p.Glu878Val	missense	N/A	NP_001171602.1	P01133-2
	EGF	NM_001357021.2		c.2390_2391delAGinsTA	p.Glu797Val	missense	N/A	NP_001343950.1	A0A494C018

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGF	ENST00000265171.10	TSL:1 MANE Select	c.2759_2760delAGinsTA	p.Glu920Val	missense	N/A	ENSP00000265171.5	P01133-1
	EGF	ENST00000503392.1	TSL:1	c.2735-1462_2735-1461delAGinsTA		intron	N/A	ENSP00000421384.1	P01133-3
	EGF	ENST00000509996.1	TSL:1	n.444_445delAGinsTA		non_coding_transcript_exon	Exon 3 of 7

Frequencies

GnomAD3 genomes Cov.: 29

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 29

GnomAD MNV AF: 0.000173 AC: 49 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.80

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-110914427;