4-109919790-A-G

Variant names:

• chr4-109919790-A-G
• rs2881559
• NM_001963.6:c.127+6328A>G

Variant summary

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

The ENST00000265171.10(EGF):​c.127+6328A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 151,170 control chromosomes in the GnomAD database, including 20,383 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 0.50 (20383 hom., cov: 31)
• Consequence: EGF ENST00000265171.10 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.97
• Publications: 3 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, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.676 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000265171.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGF	NM_001963.6	MANE Select	c.127+6328A>G		intron	N/A	NP_001954.2
	EGF	NM_001178130.3		c.127+6328A>G		intron	N/A	NP_001171601.1
	EGF	NM_001178131.3		c.127+6328A>G		intron	N/A	NP_001171602.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGF	ENST00000265171.10	TSL:1 MANE Select	c.127+6328A>G		intron	N/A	ENSP00000265171.5
	EGF	ENST00000503392.1	TSL:1	c.127+6328A>G		intron	N/A	ENSP00000421384.1
	EGF	ENST00000509793.5	TSL:2	c.127+6328A>G		intron	N/A	ENSP00000424316.1

Frequencies

GnomAD3 genomes AF: 0.497 AC: 75081 AN: 151052 Hom.: 20342 Cov.: 31

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.489

Gnomad EAS AF: 0.694

Gnomad SAS AF: 0.509

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.489

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

GnomAD4 genome AF: 0.497 AC: 75177 AN: 151170 Hom.: 20383 Cov.: 31 AF XY: 0.496 AC XY: 36674 AN XY: 73882

African (AFR) AF: 0.668 AC: 27189 AN: 40684

American (AMR) AF: 0.511 AC: 7798 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.489 AC: 1694 AN: 3466

East Asian (EAS) AF: 0.695 AC: 3578 AN: 5148

South Asian (SAS) AF: 0.510 AC: 2453 AN: 4808

European-Finnish (FIN) AF: 0.352 AC: 3722 AN: 10564

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.399 AC: 27110 AN: 67936

Other (OTH) AF: 0.494 AC: 1040 AN: 2106

Alfa AF: 0.464 Hom.: 2242

Bravo AF: 0.522

Asia WGS AF: 0.601 AC: 2091 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.69
DANN	Benign	0.32
PhyloP100		-2.0
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: rs2881559; hg19: chr4-110840946;