4-109913435-G-C

Variant names:

• chr4-109913435-G-C
• rs201626324
• NM_001963.6:c.100G>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.100G>C​(p.Ala34Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EGF NM_001963.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32

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=0.08540809).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.100G>C	p.Ala34Pro	missense_variant	Exon 1 of 24	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.100G>C	p.Ala34Pro	missense_variant	Exon 1 of 23		NP_001171601.1
EGF	NM_001178131.3	c.100G>C	p.Ala34Pro	missense_variant	Exon 1 of 23		NP_001171602.1
EGF	NM_001357021.2	c.100G>C	p.Ala34Pro	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.100G>C	p.Ala34Pro	missense_variant	Exon 1 of 24	1	NM_001963.6	ENSP00000265171.5
EGF	ENST00000503392.1	c.100G>C	p.Ala34Pro	missense_variant	Exon 1 of 23	1		ENSP00000421384.1
EGF	ENST00000509793.5	c.100G>C	p.Ala34Pro	missense_variant	Exon 1 of 23	2		ENSP00000424316.1
EGF	ENST00000652245.1	c.100G>C	p.Ala34Pro	missense_variant	Exon 1 of 20			ENSP00000498337.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249664 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135082

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.11
DANN	Benign	0.63
DEOGEN2	Benign	0.29	.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.60	T;T;T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.085	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.20	N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.26	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.80	P;B;.
Vest4		0.056
MutPred		0.44		Loss of catalytic residue at A34 (P = 0.0138);Loss of catalytic residue at A34 (P = 0.0138);Loss of catalytic residue at A34 (P = 0.0138);
MVP		0.67
MPC		0.24
ClinPred		0.090	T
GERP RS		-4.3
Varity_R		0.070
gMVP		0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs201626324; hg19: chr4-110834591;