4-109913381-A-G

Variant names:

• chr4-109913381-A-G
• rs11568849
• NM_001963.6:c.46A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001963.6(EGF):​c.46A>G​(p.Ser16Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S16R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EGF NM_001963.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.423
• Publications: 11 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1416626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.46A>G	p.Ser16Gly	missense_variant	Exon 1 of 24	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.46A>G	p.Ser16Gly	missense_variant	Exon 1 of 23		NP_001171601.1
EGF	NM_001178131.3	c.46A>G	p.Ser16Gly	missense_variant	Exon 1 of 23		NP_001171602.1
EGF	NM_001357021.2	c.46A>G	p.Ser16Gly	missense_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.46A>G	p.Ser16Gly	missense_variant	Exon 1 of 24	1	NM_001963.6	ENSP00000265171.5
EGF	ENST00000503392.1	c.46A>G	p.Ser16Gly	missense_variant	Exon 1 of 23	1		ENSP00000421384.1
EGF	ENST00000509793.5	c.46A>G	p.Ser16Gly	missense_variant	Exon 1 of 23	2		ENSP00000424316.1
EGF	ENST00000652245.1	c.46A>G	p.Ser16Gly	missense_variant	Exon 1 of 20			ENSP00000498337.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461692 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727150

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000448 AC: 2 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111894

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74318

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.000262 AC: 4 AN: 15270

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 10

Bravo AF: 0.0000340

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.2
DANN	Benign	0.82
DEOGEN2	Benign	0.35	.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.66	T;T;T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.8	L;L;L
PhyloP100		0.42
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.94	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.010	B;B;.
Vest4		0.065
MutPred		0.56		Loss of stability (P = 0.0314);Loss of stability (P = 0.0314);Loss of stability (P = 0.0314);
MVP		0.73
MPC		0.17
ClinPred		0.86	D
GERP RS		-5.5
PromoterAI		0.066	Neutral
Varity_R		0.046
gMVP		0.32
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11568849; hg19: chr4-110834537;