4-109989869-A-G

Variant names:

• chr4-109989869-A-G
• rs2237052
• NM_001963.6:c.2734+1160A>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.2734+1160A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 151,810 control chromosomes in the GnomAD database, including 23,648 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 0.52 (23648 hom., cov: 31)
• Consequence: EGF NM_001963.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.215
• Publications: 2 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.802 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.2734+1160A>G		intron_variant	Intron 18 of 23	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.2734+1160A>G		intron_variant	Intron 18 of 22		NP_001171601.1
EGF	NM_001178131.3	c.2608+1160A>G		intron_variant	Intron 17 of 22		NP_001171602.1
EGF	NM_001357021.2	c.2366-3378A>G		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+1160A>G		intron_variant	Intron 18 of 23	1	NM_001963.6	ENSP00000265171.5

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79350 AN: 151694 Hom.: 23575 Cov.: 31

Gnomad AFR AF: 0.809

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.429

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.519

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.498

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

GnomAD4 genome AF: 0.524 AC: 79490 AN: 151810 Hom.: 23648 Cov.: 31 AF XY: 0.524 AC XY: 38831 AN XY: 74134

African (AFR) AF: 0.809 AC: 33532 AN: 41432

American (AMR) AF: 0.517 AC: 7886 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 1490 AN: 3470

East Asian (EAS) AF: 0.683 AC: 3509 AN: 5134

South Asian (SAS) AF: 0.519 AC: 2491 AN: 4796

European-Finnish (FIN) AF: 0.335 AC: 3524 AN: 10504

Middle Eastern (MID) AF: 0.473 AC: 138 AN: 292

European-Non Finnish (NFE) AF: 0.375 AC: 25478 AN: 67924

Other (OTH) AF: 0.503 AC: 1061 AN: 2110

Alfa AF: 0.480 Hom.: 2601

Bravo AF: 0.553

Asia WGS AF: 0.606 AC: 2109 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.0
DANN	Benign	0.46
PhyloP100		0.21
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: rs2237052; hg19: chr4-110911025;