rs2250616

Variant names:

• chr4-109915408-G-A
• rs2250616
• NM_001963.6:c.127+1946G>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+1946G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 151,938 control chromosomes in the GnomAD database, including 6,692 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 0.29 (6692 hom., cov: 32)
• Consequence: EGF NM_001963.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.519
• 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, AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.327 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.127+1946G>A		intron	N/A	NP_001954.2	P01133-1
	EGF	NM_001178130.3		c.127+1946G>A		intron	N/A	NP_001171601.1	P01133-3
	EGF	NM_001178131.3		c.127+1946G>A		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.127+1946G>A		intron	N/A	ENSP00000265171.5	P01133-1
	EGF	ENST00000503392.1	TSL:1	c.127+1946G>A		intron	N/A	ENSP00000421384.1	P01133-3
	EGF	ENST00000868530.1		c.127+1946G>A		intron	N/A	ENSP00000538589.1

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43882 AN: 151820 Hom.: 6692 Cov.: 32

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.0843

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.311

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

GnomAD4 genome AF: 0.289 AC: 43896 AN: 151938 Hom.: 6692 Cov.: 32 AF XY: 0.283 AC XY: 20999 AN XY: 74244

African (AFR) AF: 0.251 AC: 10405 AN: 41420

American (AMR) AF: 0.261 AC: 3981 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1323 AN: 3468

East Asian (EAS) AF: 0.0849 AC: 439 AN: 5172

South Asian (SAS) AF: 0.222 AC: 1065 AN: 4804

European-Finnish (FIN) AF: 0.300 AC: 3165 AN: 10546

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.330 AC: 22457 AN: 67952

Other (OTH) AF: 0.308 AC: 649 AN: 2104

Alfa AF: 0.311 Hom.: 1300

Bravo AF: 0.287

Asia WGS AF: 0.159 AC: 557 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.0
DANN	Benign	0.75
PhyloP100		-0.52
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

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

Other links and lift over

dbSNP: rs2250616;

hg19: chr4-110836564;