chr4-109970517-T-C

Variant names:

• chr4-109970517-T-C
• rs2298989
• NM_001963.6:c.1724+1398T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001963.6(EGF):​c.1724+1398T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 151,950 control chromosomes in the GnomAD database, including 26,569 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (26569 hom., cov: 30)
• Consequence: EGF NM_001963.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• Publications: 10 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: Unknown, AR, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

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.1724+1398T>C		intron	N/A	NP_001954.2	P01133-1
	EGF	NM_001178130.3		c.1724+1398T>C		intron	N/A	NP_001171601.1	P01133-3
	EGF	NM_001178131.3		c.1598+1398T>C		intron	N/A	NP_001171602.1	P01133-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGF	ENST00000265171.10	TSL:1 MANE Select	c.1724+1398T>C		intron	N/A	ENSP00000265171.5	P01133-1
	EGF	ENST00000503392.1	TSL:1	c.1724+1398T>C		intron	N/A	ENSP00000421384.1	P01133-3
	EGF	ENST00000868530.1		c.1724+1398T>C		intron	N/A	ENSP00000538589.1

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85206 AN: 151832 Hom.: 26498 Cov.: 30

Gnomad AFR AF: 0.833

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.548

Gnomad ASJ AF: 0.516

Gnomad EAS AF: 0.702

Gnomad SAS AF: 0.497

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.545

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

GnomAD4 genome AF: 0.562 AC: 85336 AN: 151950 Hom.: 26569 Cov.: 30 AF XY: 0.560 AC XY: 41576 AN XY: 74280

African (AFR) AF: 0.834 AC: 34573 AN: 41458

American (AMR) AF: 0.548 AC: 8362 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 1790 AN: 3472

East Asian (EAS) AF: 0.703 AC: 3624 AN: 5156

South Asian (SAS) AF: 0.498 AC: 2392 AN: 4808

European-Finnish (FIN) AF: 0.372 AC: 3928 AN: 10550

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.425 AC: 28884 AN: 67916

Other (OTH) AF: 0.549 AC: 1160 AN: 2112

Alfa AF: 0.480 Hom.: 24223

Bravo AF: 0.590

Asia WGS AF: 0.631 AC: 2199 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.41
DANN	Benign	0.68
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2298989; hg19: chr4-110891673;