chr4-109913196-A-G

Variant names:

• chr4-109913196-A-G
• rs543779474
• NM_001963.6:c.-140A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001963.6(EGF):​c.-140A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000803 in 1,008,572 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: EGF NM_001963.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02
• 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: Unknown, AR, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS2: High AC in GnomAd4 at 14 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGF	NM_001963.6	MANE Select	c.-140A>G		5_prime_UTR	Exon 1 of 24	NP_001954.2	P01133-1
	EGF	NM_001178130.3		c.-140A>G		5_prime_UTR	Exon 1 of 23	NP_001171601.1	P01133-3
	EGF	NM_001178131.3		c.-140A>G		5_prime_UTR	Exon 1 of 23	NP_001171602.1	P01133-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGF	ENST00000265171.10	TSL:1 MANE Select	c.-140A>G		5_prime_UTR	Exon 1 of 24	ENSP00000265171.5	P01133-1
	EGF	ENST00000868530.1		c.-140A>G		5_prime_UTR	Exon 1 of 24	ENSP00000538589.1
	EGF	ENST00000868531.1		c.-140A>G		5_prime_UTR	Exon 1 of 24	ENSP00000538590.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000782 AC: 67 AN: 856232 Hom.: 0 Cov.: 11 AF XY: 0.0000828 AC XY: 37 AN XY: 446802

African (AFR) AF: 0.00 AC: 0 AN: 21492

American (AMR) AF: 0.00 AC: 0 AN: 38984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20714

East Asian (EAS) AF: 0.00 AC: 0 AN: 34506

South Asian (SAS) AF: 0.00 AC: 0 AN: 70092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4460

European-Non Finnish (NFE) AF: 0.000111 AC: 65 AN: 586640

Other (OTH) AF: 0.0000505 AC: 2 AN: 39590

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74492

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000121

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Renal hypomagnesemia 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.9
DANN	Benign	0.44
PhyloP100		1.0
PromoterAI		-0.010	Neutral

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: rs543779474; hg19: chr4-110834352;