4-110006407-G-C

Variant names:

• chr4-110006407-G-C
• rs6533485
• NM_001963.6:c.3292-1745G>C

Variant summary

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

The NM_001963.6(EGF):​c.3292-1745G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 151,990 control chromosomes in the GnomAD database, including 30,997 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 0.61 (30997 hom., cov: 31)
• Consequence: EGF NM_001963.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.198
• Publications: 8 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.889 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGF	NM_001963.6	MANE Select	c.3292-1745G>C		intron	N/A	NP_001954.2
	EGF	NM_001178130.3		c.3169-1745G>C		intron	N/A	NP_001171601.1
	EGF	NM_001178131.3		c.3166-1745G>C		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.3292-1745G>C		intron	N/A	ENSP00000265171.5
	EGF	ENST00000503392.1	TSL:1	c.3169-1745G>C		intron	N/A	ENSP00000421384.1
	EGF	ENST00000509996.1	TSL:1	n.976+1785G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.609 AC: 92537 AN: 151868 Hom.: 30923 Cov.: 31

Gnomad AFR AF: 0.896

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.538

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.631

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.465

Gnomad OTH AF: 0.570

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

GnomAD4 genome AF: 0.610 AC: 92673 AN: 151990 Hom.: 30997 Cov.: 31 AF XY: 0.611 AC XY: 45351 AN XY: 74250

African (AFR) AF: 0.896 AC: 37204 AN: 41512

American (AMR) AF: 0.571 AC: 8726 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.538 AC: 1866 AN: 3470

East Asian (EAS) AF: 0.704 AC: 3627 AN: 5150

South Asian (SAS) AF: 0.631 AC: 3033 AN: 4808

European-Finnish (FIN) AF: 0.458 AC: 4817 AN: 10524

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.465 AC: 31570 AN: 67944

Other (OTH) AF: 0.575 AC: 1213 AN: 2108

Alfa AF: 0.415 Hom.: 1415

Bravo AF: 0.632

Asia WGS AF: 0.687 AC: 2391 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.5
DANN	Benign	0.81
PhyloP100		-0.20
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: rs6533485; hg19: chr4-110927563;