chr4-109954434-C-G

Variant names:

• chr4-109954434-C-G
• rs1024600
• NM_001963.6:c.941-4878C>G

Variant summary

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

The NM_001963.6(EGF):​c.941-4878C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 152,020 control chromosomes in the GnomAD database, including 5,528 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 0.26 (5528 hom., cov: 32)
• Consequence: EGF NM_001963.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.539
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.307 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.941-4878C>G		intron	N/A	NP_001954.2
	EGF	NM_001178130.3		c.941-4878C>G		intron	N/A	NP_001171601.1
	EGF	NM_001178131.3		c.941-6433C>G		intron	N/A	NP_001171602.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGF	ENST00000265171.10	TSL:1 MANE Select	c.941-4878C>G		intron	N/A	ENSP00000265171.5
	EGF	ENST00000503392.1	TSL:1	c.941-4878C>G		intron	N/A	ENSP00000421384.1
	EGF	ENST00000868530.1		c.941-4878C>G		intron	N/A	ENSP00000538589.1

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39522 AN: 151902 Hom.: 5532 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.0845

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.278

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

GnomAD4 genome AF: 0.260 AC: 39520 AN: 152020 Hom.: 5528 Cov.: 32 AF XY: 0.255 AC XY: 18923 AN XY: 74302

African (AFR) AF: 0.197 AC: 8189 AN: 41474

American (AMR) AF: 0.231 AC: 3526 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 1224 AN: 3468

East Asian (EAS) AF: 0.0851 AC: 440 AN: 5170

South Asian (SAS) AF: 0.216 AC: 1041 AN: 4816

European-Finnish (FIN) AF: 0.291 AC: 3067 AN: 10540

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21116 AN: 67956

Other (OTH) AF: 0.275 AC: 581 AN: 2110

Alfa AF: 0.184 Hom.: 440

Bravo AF: 0.254

Asia WGS AF: 0.151 AC: 527 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.48
DANN	Benign	0.38
PhyloP100		-0.54
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: rs1024600; hg19: chr4-110875590;