chr4-109912994-C-G

Variant names:

• chr4-109912994-C-G
• rs11568847
• NM_001963.6:c.-342C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001963.6(EGF):​c.-342C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 303,394 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 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: EGF NM_001963.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0270
• 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: Unknown, AR, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 8 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.-342C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 24	NP_001954.2	P01133-1
	EGF	NM_001963.6	MANE Select	c.-342C>G		5_prime_UTR	Exon 1 of 24	NP_001954.2	P01133-1
	EGF	NM_001178130.3		c.-342C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 23	NP_001171601.1	P01133-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGF	ENST00000265171.10	TSL:1 MANE Select	c.-342C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 24	ENSP00000265171.5	P01133-1
	EGF	ENST00000265171.10	TSL:1 MANE Select	c.-342C>G		5_prime_UTR	Exon 1 of 24	ENSP00000265171.5	P01133-1
	EGF	ENST00000868530.1		c.-342C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 24	ENSP00000538589.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152198 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: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000530 AC: 8 AN: 151078 Hom.: 0 Cov.: 0 AF XY: 0.0000497 AC XY: 4 AN XY: 80480

African (AFR) AF: 0.00 AC: 0 AN: 4582

American (AMR) AF: 0.00 AC: 0 AN: 6900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3714

East Asian (EAS) AF: 0.000981 AC: 7 AN: 7136

South Asian (SAS) AF: 0.00 AC: 0 AN: 24736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 588

European-Non Finnish (NFE) AF: 0.0000113 AC: 1 AN: 88756

Other (OTH) AF: 0.00 AC: 0 AN: 7658

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74482

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

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: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 12

Bravo AF: 0.0000869

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	-0.68
CADD	Benign	16
DANN	Benign	0.77
PhyloP100		-0.027
PromoterAI		0.056	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.35		Position offset: -1

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

Other links and lift over

dbSNP: rs11568847; hg19: chr4-110834150;