NM_001963.6:c.2491+1106A>G

Variant names:

• chr4-109984647-A-G
• rs11569033
• NM_001963.6:c.2491+1106A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001963.6(EGF):​c.2491+1106A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 152,292 control chromosomes in the GnomAD database, including 23 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 0.013 (23 hom., cov: 32)
• Consequence: EGF NM_001963.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0390
• Publications: 4 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).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0126 (1926/152292) while in subpopulation NFE AF = 0.017 (1157/68022). AF 95% confidence interval is 0.0162. There are 23 homozygotes in GnomAd4. There are 940 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1926 AD,Unknown gene.

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.2491+1106A>G		intron	N/A	NP_001954.2
	EGF	NM_001178130.3		c.2491+1106A>G		intron	N/A	NP_001171601.1
	EGF	NM_001178131.3		c.2365+1106A>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.2491+1106A>G		intron	N/A	ENSP00000265171.5
	EGF	ENST00000503392.1	TSL:1	c.2491+1106A>G		intron	N/A	ENSP00000421384.1
	EGF	ENST00000509996.1	TSL:1	n.419+1106A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1924 AN: 152174 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0232

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0182

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

GnomAD4 genome AF: 0.0126 AC: 1926 AN: 152292 Hom.: 23 Cov.: 32 AF XY: 0.0126 AC XY: 940 AN XY: 74472

African (AFR) AF: 0.00279 AC: 116 AN: 41574

American (AMR) AF: 0.0129 AC: 197 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4822

European-Finnish (FIN) AF: 0.0232 AC: 246 AN: 10614

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0170 AC: 1157 AN: 68022

Other (OTH) AF: 0.0185 AC: 39 AN: 2112

Alfa AF: 0.0159 Hom.: 31

Bravo AF: 0.0116

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.9
DANN	Benign	0.67
PhyloP100		-0.039
Mutation Taster		=100/0	polymorphism

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: rs11569033; hg19: chr4-110905803;