4-109912889-G-A

Variant names:

• chr4-109912889-G-A
• rs56399752
• NM_001963.6:c.-447G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001963.6(EGF):​c.-447G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000776 in 179,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: EGF NM_001963.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.31
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 4-109912889-G-A is Benign according to our data. Variant chr4-109912889-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 347218.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 124 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.-447G>A		5_prime_UTR_variant	Exon 1 of 24	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.-447G>A		5_prime_UTR_variant	Exon 1 of 23		NP_001171601.1
EGF	NM_001178131.3	c.-447G>A		5_prime_UTR_variant	Exon 1 of 23		NP_001171602.1
EGF	NM_001357021.2	c.-447G>A		5_prime_UTR_variant	Exon 1 of 20		NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10	c.-447G>A		5_prime_UTR_variant	Exon 1 of 24	1	NM_001963.6	ENSP00000265171.5
EGF	ENST00000509793.5	c.-447G>A		5_prime_UTR_variant	Exon 1 of 23	2		ENSP00000424316.1
EGF	ENST00000652245.1	c.-447G>A		5_prime_UTR_variant	Exon 1 of 20			ENSP00000498337.1

Frequencies

GnomAD3 genomes AF: 0.000821 AC: 125 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000560 AC: 15 AN: 26766 Hom.: 0 Cov.: 0 AF XY: 0.000444 AC XY: 6 AN XY: 13510

African (AFR) AF: 0.00 AC: 0 AN: 392

American (AMR) AF: 0.00204 AC: 6 AN: 2944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 460

East Asian (EAS) AF: 0.00 AC: 0 AN: 1552

South Asian (SAS) AF: 0.00 AC: 0 AN: 2894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 62

European-Non Finnish (NFE) AF: 0.000436 AC: 7 AN: 16044

Other (OTH) AF: 0.00139 AC: 2 AN: 1438

GnomAD4 genome AF: 0.000814 AC: 124 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.000846 AC XY: 63 AN XY: 74482

African (AFR) AF: 0.000770 AC: 32 AN: 41570

American (AMR) AF: 0.00294 AC: 45 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000971 Hom.: 0

Bravo AF: 0.00121

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal hypomagnesemia 4 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.88
PhyloP100		3.3
PromoterAI		-0.12	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs56399752; hg19: chr4-110834045;