rs881878

Variant names:

• chr4-109914892-G-A
• rs881878
• NM_001963.6:c.127+1430G>A

Variant summary

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

The NM_001963.6(EGF):​c.127+1430G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 152,124 control chromosomes in the GnomAD database, including 5,414 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 0.24 (5414 hom., cov: 32)
• Consequence: EGF NM_001963.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00500
• Publications: 9 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.127+1430G>A		intron_variant	Intron 1 of 23	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.127+1430G>A		intron_variant	Intron 1 of 22		NP_001171601.1
EGF	NM_001178131.3	c.127+1430G>A		intron_variant	Intron 1 of 22		NP_001171602.1
EGF	NM_001357021.2	c.127+1430G>A		intron_variant	Intron 1 of 19		NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10	c.127+1430G>A		intron_variant	Intron 1 of 23	1	NM_001963.6	ENSP00000265171.5
EGF	ENST00000503392.1	c.127+1430G>A		intron_variant	Intron 1 of 22	1		ENSP00000421384.1
EGF	ENST00000509793.5	c.127+1430G>A		intron_variant	Intron 1 of 22	2		ENSP00000424316.1
EGF	ENST00000652245.1	c.127+1430G>A		intron_variant	Intron 1 of 19			ENSP00000498337.1

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36720 AN: 152006 Hom.: 5417 Cov.: 32

Gnomad AFR AF: 0.0894

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.0846

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.280

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

GnomAD4 genome AF: 0.241 AC: 36716 AN: 152124 Hom.: 5414 Cov.: 32 AF XY: 0.237 AC XY: 17630 AN XY: 74352

African (AFR) AF: 0.0891 AC: 3704 AN: 41552

American (AMR) AF: 0.242 AC: 3700 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1285 AN: 3466

East Asian (EAS) AF: 0.0852 AC: 441 AN: 5176

South Asian (SAS) AF: 0.221 AC: 1063 AN: 4810

European-Finnish (FIN) AF: 0.299 AC: 3153 AN: 10562

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.330 AC: 22406 AN: 67960

Other (OTH) AF: 0.277 AC: 585 AN: 2110

Alfa AF: 0.278 Hom.: 1196

Bravo AF: 0.233

Asia WGS AF: 0.148 AC: 519 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.3
DANN	Benign	0.63
PhyloP100		0.0050
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: rs881878; hg19: chr4-110836048;