chr4-109913435-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001963.6(EGF):​c.100G>A​(p.Ala34Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

EGF
NM_001963.6 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.32
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.046546787).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EGFNM_001963.6 linkuse as main transcriptc.100G>A p.Ala34Thr missense_variant 1/24 ENST00000265171.10
EGFNM_001178130.3 linkuse as main transcriptc.100G>A p.Ala34Thr missense_variant 1/23
EGFNM_001178131.3 linkuse as main transcriptc.100G>A p.Ala34Thr missense_variant 1/23
EGFNM_001357021.2 linkuse as main transcriptc.100G>A p.Ala34Thr missense_variant 1/20

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EGFENST00000265171.10 linkuse as main transcriptc.100G>A p.Ala34Thr missense_variant 1/241 NM_001963.6 P1P01133-1
EGFENST00000503392.1 linkuse as main transcriptc.100G>A p.Ala34Thr missense_variant 1/231 P01133-3
EGFENST00000509793.5 linkuse as main transcriptc.100G>A p.Ala34Thr missense_variant 1/232 P01133-2
EGFENST00000652245.1 linkuse as main transcriptc.100G>A p.Ala34Thr missense_variant 1/20

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152106
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
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
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
249664
Hom.:
0
AF XY:
0.0000296
AC XY:
4
AN XY:
135082
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000356
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461536
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727056
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152224
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74424
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 11, 2023This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 34 of the EGF protein (p.Ala34Thr). This variant is present in population databases (rs201626324, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with EGF-related conditions. ClinVar contains an entry for this variant (Variation ID: 2042096). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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
0.078
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
0.20
DANN
Benign
0.69
DEOGEN2
Benign
0.30
.;T;.
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.085
N
LIST_S2
Benign
0.75
T;T;T
M_CAP
Uncertain
0.087
D
MetaRNN
Benign
0.047
T;T;T
MetaSVM
Benign
-0.65
T
MutationAssessor
Benign
0.20
N;N;N
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.21
T
PROVEAN
Benign
-0.46
N;N;N
REVEL
Benign
0.089
Sift
Benign
0.41
T;T;T
Sift4G
Benign
0.29
T;T;T
Polyphen
0.47
P;B;.
Vest4
0.092
MVP
0.66
MPC
0.18
ClinPred
0.018
T
GERP RS
-4.3
Varity_R
0.022
gMVP
0.25

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201626324; hg19: chr4-110834591; COSMIC: COSV54483787; API