Genetic Variant EGF:p.Ala34Pro (chr4-109913435-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_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. 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. A34T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

EGF
NM_001963.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.32

Publications

7 publications found

Variant links:

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

EGF links:

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ACMG classification

Classification was made for transcript

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=0.08540809).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EGF	NM_001963.6	MANE Select	c.100G>C	p.Ala34Pro	missense	Exon 1 of 24	NP_001954.2	P01133-1
EGF	NM_001178130.3		c.100G>C	p.Ala34Pro	missense	Exon 1 of 23	NP_001171601.1	P01133-3
EGF	NM_001178131.3		c.100G>C	p.Ala34Pro	missense	Exon 1 of 23	NP_001171602.1	P01133-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EGF	ENST00000265171.10	TSL:1 MANE Select	c.100G>C	p.Ala34Pro	missense	Exon 1 of 24	ENSP00000265171.5	P01133-1
EGF	ENST00000503392.1	TSL:1	c.100G>C	p.Ala34Pro	missense	Exon 1 of 23	ENSP00000421384.1	P01133-3
EGF	ENST00000868530.1		c.100G>C	p.Ala34Pro	missense	Exon 1 of 24	ENSP00000538589.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249664

AF XY:

0.00

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000891

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.11

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.29

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.60

M_CAP

Benign

0.076

MetaRNN

Benign

0.085

MetaSVM

Benign

-0.61

MutationAssessor

Benign

0.20

PhyloP100

-1.3

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.26

REVEL

Benign

0.15

Sift

Benign

0.29

Sift4G

Benign

0.28

Polyphen

0.80

Vest4

0.056

MutPred

0.44

Loss of catalytic residue at A34 (P = 0.0138)

MVP

0.67

MPC

0.24

ClinPred

0.090

GERP RS

-4.3

PromoterAI

-0.059

Neutral

(source)

Varity_R

0.070

gMVP

0.72

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over