4-109970856-T-G

Variant names:

• chr4-109970856-T-G
• rs2298991
• NM_001963.6:c.1724+1737T>G

Variant summary

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

The ENST00000265171.10(EGF):​c.1724+1737T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 147,300 control chromosomes in the GnomAD database, including 24,633 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 0.54 (24633 hom., cov: 27)
• Consequence: EGF ENST00000265171.10 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.93
• Publications: 6 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.826 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.1724+1737T>G		intron	N/A	NP_001954.2
	EGF	NM_001178130.3		c.1724+1737T>G		intron	N/A	NP_001171601.1
	EGF	NM_001178131.3		c.1598+1737T>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.1724+1737T>G		intron	N/A	ENSP00000265171.5
	EGF	ENST00000503392.1	TSL:1	c.1724+1737T>G		intron	N/A	ENSP00000421384.1
	EGF	ENST00000509793.5	TSL:2	c.1598+1737T>G		intron	N/A	ENSP00000424316.1

Frequencies

GnomAD3 genomes AF: 0.544 AC: 80137 AN: 147204 Hom.: 24579 Cov.: 27

Gnomad AFR AF: 0.833

Gnomad AMI AF: 0.484

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.735

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.474

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.527

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

GnomAD4 genome AF: 0.545 AC: 80240 AN: 147300 Hom.: 24633 Cov.: 27 AF XY: 0.543 AC XY: 38853 AN XY: 71496

African (AFR) AF: 0.833 AC: 32478 AN: 38972

American (AMR) AF: 0.526 AC: 7739 AN: 14720

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1700 AN: 3450

East Asian (EAS) AF: 0.736 AC: 3626 AN: 4926

South Asian (SAS) AF: 0.497 AC: 2323 AN: 4678

European-Finnish (FIN) AF: 0.368 AC: 3568 AN: 9692

Middle Eastern (MID) AF: 0.468 AC: 133 AN: 284

European-Non Finnish (NFE) AF: 0.401 AC: 27159 AN: 67646

Other (OTH) AF: 0.530 AC: 1079 AN: 2034

Alfa AF: 0.460 Hom.: 11213

Bravo AF: 0.581

Asia WGS AF: 0.651 AC: 2266 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.66
DANN	Benign	0.30
PhyloP100		-1.9
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: rs2298991; hg19: chr4-110892012;