rs11568993

Variant names:

• chr4-109976159-C-T
• rs11568993
• NM_001963.6:c.1977C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-109976159-C-T
• chr4-109976159-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001963.6(EGF):​c.1977C>T​(p.Cys659Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0714 in 1,614,006 control chromosomes in the GnomAD database, including 4,842 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (334 hom., cov: 33)
  • Exomes 𝑓: 0.073 (4508 hom.)
• Consequence: EGF NM_001963.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.24
• Publications: 15 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 4-109976159-C-T is Benign according to our data. Variant chr4-109976159-C-T is described in ClinVar as Benign. ClinVar VariationId is 347241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0758 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.1977C>T	p.Cys659Cys	synonymous	Exon 13 of 24	NP_001954.2	P01133-1
	EGF	NM_001178130.3		c.1977C>T	p.Cys659Cys	synonymous	Exon 13 of 23	NP_001171601.1	P01133-3
	EGF	NM_001178131.3		c.1851C>T	p.Cys617Cys	synonymous	Exon 12 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.1977C>T	p.Cys659Cys	synonymous	Exon 13 of 24	ENSP00000265171.5	P01133-1
	EGF	ENST00000503392.1	TSL:1	c.1977C>T	p.Cys659Cys	synonymous	Exon 13 of 23	ENSP00000421384.1	P01133-3
	EGF	ENST00000868530.1		c.1977C>T	p.Cys659Cys	synonymous	Exon 13 of 24	ENSP00000538589.1

Frequencies

GnomAD3 genomes AF: 0.0528 AC: 8035 AN: 152132 Hom.: 333 Cov.: 33

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0536

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0158

Gnomad FIN AF: 0.0610

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0776

Gnomad OTH AF: 0.0630

GnomAD2 exomes AF: 0.0563 AC: 14140 AN: 251270 AF XY: 0.0569

Gnomad AFR exome AF: 0.0116

Gnomad AMR exome AF: 0.0454

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0566

Gnomad NFE exome AF: 0.0772

Gnomad OTH exome AF: 0.0727

GnomAD4 exome AF: 0.0734 AC: 107267 AN: 1461756 Hom.: 4508 Cov.: 32 AF XY: 0.0717 AC XY: 52116 AN XY: 727182

African (AFR) AF: 0.0123 AC: 413 AN: 33478

American (AMR) AF: 0.0470 AC: 2103 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 3535 AN: 26132

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39696

South Asian (SAS) AF: 0.0194 AC: 1671 AN: 86254

European-Finnish (FIN) AF: 0.0576 AC: 3079 AN: 53416

Middle Eastern (MID) AF: 0.0845 AC: 487 AN: 5764

European-Non Finnish (NFE) AF: 0.0823 AC: 91541 AN: 1111922

Other (OTH) AF: 0.0734 AC: 4430 AN: 60394

GnomAD4 genome AF: 0.0528 AC: 8032 AN: 152250 Hom.: 334 Cov.: 33 AF XY: 0.0507 AC XY: 3773 AN XY: 74438

African (AFR) AF: 0.0134 AC: 556 AN: 41544

American (AMR) AF: 0.0535 AC: 819 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 466 AN: 3472

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

South Asian (SAS) AF: 0.0160 AC: 77 AN: 4814

European-Finnish (FIN) AF: 0.0610 AC: 646 AN: 10598

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0775 AC: 5273 AN: 68020

Other (OTH) AF: 0.0624 AC: 132 AN: 2116

Alfa AF: 0.0713 Hom.: 1518

Bravo AF: 0.0533

Asia WGS AF: 0.0140 AC: 51 AN: 3478

EpiCase AF: 0.0872

EpiControl AF: 0.0875

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Renal hypomagnesemia 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	5.5
DANN	Benign	0.51
PhyloP100		-1.2
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: rs11568993; hg19: chr4-110897315; COSMIC: COSV54480122; COSMIC: COSV54480122;