4-109913376-A-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001963.6(EGF):​c.41A>C​(p.Lys14Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EGF NM_001963.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.249

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15233237).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.41A>C	p.Lys14Thr	missense_variant	Exon 1 of 24	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.41A>C	p.Lys14Thr	missense_variant	Exon 1 of 23		NP_001171601.1
EGF	NM_001178131.3	c.41A>C	p.Lys14Thr	missense_variant	Exon 1 of 23		NP_001171602.1
EGF	NM_001357021.2	c.41A>C	p.Lys14Thr	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>C	p.Lys14Thr	missense_variant	Exon 1 of 24	1	NM_001963.6	ENSP00000265171.5
EGF	ENST00000503392.1	c.41A>C	p.Lys14Thr	missense_variant	Exon 1 of 23	1		ENSP00000421384.1
EGF	ENST00000509793.5	c.41A>C	p.Lys14Thr	missense_variant	Exon 1 of 23	2		ENSP00000424316.1
EGF	ENST00000652245.1	c.41A>C	p.Lys14Thr	missense_variant	Exon 1 of 20			ENSP00000498337.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251202 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461708 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727162

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 14 of the EGF protein (p.Lys14Thr). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with EGF-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	1.6
DANN	Benign	0.79
DEOGEN2	Benign	0.38	.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.8	L;L;L
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.23
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.42	T;T;T
Polyphen		0.11	B;B;.
Vest4		0.15
MutPred		0.58		Loss of methylation at K14 (P = 0.006);Loss of methylation at K14 (P = 0.006);Loss of methylation at K14 (P = 0.006);
MVP		0.72
MPC		0.22
ClinPred		0.064	T
GERP RS		-5.0
Varity_R		0.045
gMVP		0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs749456740; hg19: chr4-110834532;