4-109961965-G-C

Variant names:

• chr4-109961965-G-C
• rs11568943
• NM_001963.6:c.1292G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001963.6(EGF):​c.1292G>C​(p.Arg431Thr) 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 1,461,554 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. R431K) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EGF NM_001963.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.63
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055503637).

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.1292G>C	p.Arg431Thr	missense	Exon 8 of 24	NP_001954.2	P01133-1
	EGF	NM_001178130.3		c.1292G>C	p.Arg431Thr	missense	Exon 8 of 23	NP_001171601.1	P01133-3
	EGF	NM_001178131.3		c.1166G>C	p.Arg389Thr	missense	Exon 7 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.1292G>C	p.Arg431Thr	missense	Exon 8 of 24	ENSP00000265171.5	P01133-1
	EGF	ENST00000503392.1	TSL:1	c.1292G>C	p.Arg431Thr	missense	Exon 8 of 23	ENSP00000421384.1	P01133-3
	EGF	ENST00000868530.1		c.1292G>C	p.Arg431Thr	missense	Exon 8 of 24	ENSP00000538589.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461554 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727084

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111786

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	2.7
DANN	Benign	0.54
DEOGEN2	Benign	0.27	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.065	N
PhyloP100		-1.6
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.18
Sift	Benign	0.44	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.095
MutPred		0.24		Gain of glycosylation at T435 (P = 0.0676)
MVP		0.57
MPC		0.27
ClinPred		0.064	T
GERP RS		-2.8
Varity_R		0.045
gMVP		0.33
Mutation Taster		=90/10	polymorphism

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: rs11568943; hg19: chr4-110883121;