4-109983292-C-T

Variant names:

• chr4-109983292-C-T
• rs6824594
• NM_001963.6:c.2372-130C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001963.6(EGF):​c.2372-130C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 1,087,190 control chromosomes in the GnomAD database, including 111,869 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.52 (23705 hom., cov: 32)
  • Exomes 𝑓: 0.42 (88164 hom.)
• Consequence: EGF NM_001963.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.712
• Publications: 6 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 4-109983292-C-T is Benign according to our data. Variant chr4-109983292-C-T is described in ClinVar as Benign. ClinVar VariationId is 1250332.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

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.2372-130C>T		intron	N/A	NP_001954.2	P01133-1
	EGF	NM_001178130.3		c.2372-130C>T		intron	N/A	NP_001171601.1	P01133-3
	EGF	NM_001178131.3		c.2246-130C>T		intron	N/A	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.2372-130C>T		intron	N/A	ENSP00000265171.5	P01133-1
	EGF	ENST00000503392.1	TSL:1	c.2372-130C>T		intron	N/A	ENSP00000421384.1	P01133-3
	EGF	ENST00000509996.1	TSL:1	n.300-130C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79539 AN: 151942 Hom.: 23631 Cov.: 32

Gnomad AFR AF: 0.810

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.500

GnomAD4 exome AF: 0.423 AC: 395838 AN: 935130 Hom.: 88164 AF XY: 0.423 AC XY: 202229 AN XY: 478304

African (AFR) AF: 0.828 AC: 18611 AN: 22482

American (AMR) AF: 0.536 AC: 17863 AN: 33328

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 9859 AN: 20914

East Asian (EAS) AF: 0.684 AC: 22078 AN: 32258

South Asian (SAS) AF: 0.473 AC: 31848 AN: 67288

European-Finnish (FIN) AF: 0.342 AC: 12509 AN: 36570

Middle Eastern (MID) AF: 0.451 AC: 1523 AN: 3380

European-Non Finnish (NFE) AF: 0.387 AC: 262111 AN: 676788

Other (OTH) AF: 0.461 AC: 19436 AN: 42122

GnomAD4 genome AF: 0.524 AC: 79680 AN: 152060 Hom.: 23705 Cov.: 32 AF XY: 0.523 AC XY: 38884 AN XY: 74338

African (AFR) AF: 0.810 AC: 33612 AN: 41492

American (AMR) AF: 0.517 AC: 7898 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1603 AN: 3466

East Asian (EAS) AF: 0.671 AC: 3474 AN: 5176

South Asian (SAS) AF: 0.480 AC: 2312 AN: 4820

European-Finnish (FIN) AF: 0.337 AC: 3561 AN: 10562

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.377 AC: 25630 AN: 67960

Other (OTH) AF: 0.504 AC: 1066 AN: 2114

Alfa AF: 0.456 Hom.: 4393

Bravo AF: 0.554

Asia WGS AF: 0.589 AC: 2050 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.81
DANN	Benign	0.48
PhyloP100		-0.71
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: rs6824594; hg19: chr4-110904448;