4-109913376-A-G

Variant names:

• chr4-109913376-A-G
• rs749456740
• NM_001963.6:c.41A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001963.6(EGF):​c.41A>G​(p.Lys14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. K14T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: EGF NM_001963.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.249
• Publications: 4 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16149074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.41A>G	p.Lys14Arg	missense_variant	Exon 1 of 24	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.41A>G	p.Lys14Arg	missense_variant	Exon 1 of 23		NP_001171601.1
EGF	NM_001178131.3	c.41A>G	p.Lys14Arg	missense_variant	Exon 1 of 23		NP_001171602.1
EGF	NM_001357021.2	c.41A>G	p.Lys14Arg	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.41A>G	p.Lys14Arg	missense_variant	Exon 1 of 24	1	NM_001963.6	ENSP00000265171.5
EGF	ENST00000503392.1	c.41A>G	p.Lys14Arg	missense_variant	Exon 1 of 23	1		ENSP00000421384.1
EGF	ENST00000509793.5	c.41A>G	p.Lys14Arg	missense_variant	Exon 1 of 23	2		ENSP00000424316.1
EGF	ENST00000652245.1	c.41A>G	p.Lys14Arg	missense_variant	Exon 1 of 20			ENSP00000498337.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251202 AF XY: 0.00

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15278

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: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	2.3
DANN	Benign	0.96
DEOGEN2	Uncertain	0.46	.;T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.1	M;M;M
PhyloP100		0.25
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.52	N;N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.020	D;D;D
Sift4G	Benign	0.069	T;T;T
Polyphen		0.62	P;P;.
Vest4		0.080
MutPred		0.56		Loss of methylation at K14 (P = 0.0075);Loss of methylation at K14 (P = 0.0075);Loss of methylation at K14 (P = 0.0075);
MVP		0.82
MPC		0.15
ClinPred		0.077	T
GERP RS		-5.0
PromoterAI		0.039	Neutral
Varity_R		0.038
gMVP		0.30
Mutation Taster		=99/1	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: rs749456740; hg19: chr4-110834532;