rs2298999

Variant names:

• chr4-109990751-T-C
• rs2298999
• NM_001963.6:c.2734+2042T>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.2734+2042T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 152,012 control chromosomes in the GnomAD database, including 25,564 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 0.55 (25564 hom., cov: 31)
• Consequence: EGF NM_001963.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.20
• Publications: 15 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.2734+2042T>C		intron_variant	Intron 18 of 23	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.2734+2042T>C		intron_variant	Intron 18 of 22		NP_001171601.1
EGF	NM_001178131.3	c.2608+2042T>C		intron_variant	Intron 17 of 22		NP_001171602.1
EGF	NM_001357021.2	c.2366-2496T>C		intron_variant	Intron 15 of 19		NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10	c.2734+2042T>C		intron_variant	Intron 18 of 23	1	NM_001963.6	ENSP00000265171.5

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83380 AN: 151892 Hom.: 25497 Cov.: 31

Gnomad AFR AF: 0.813

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.759

Gnomad SAS AF: 0.641

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.517

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

GnomAD4 genome AF: 0.549 AC: 83511 AN: 152012 Hom.: 25564 Cov.: 31 AF XY: 0.550 AC XY: 40873 AN XY: 74302

African (AFR) AF: 0.814 AC: 33766 AN: 41502

American (AMR) AF: 0.524 AC: 8008 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 1673 AN: 3470

East Asian (EAS) AF: 0.759 AC: 3908 AN: 5148

South Asian (SAS) AF: 0.640 AC: 3088 AN: 4822

European-Finnish (FIN) AF: 0.379 AC: 3998 AN: 10552

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.404 AC: 27445 AN: 67924

Other (OTH) AF: 0.522 AC: 1102 AN: 2112

Alfa AF: 0.440 Hom.: 19726

Bravo AF: 0.574

Asia WGS AF: 0.708 AC: 2462 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.6
DANN	Benign	0.64
PhyloP100		-2.2
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: rs2298999; hg19: chr4-110911907;