4-109913435-G-T

Variant summary

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

The NM_001963.6(EGF):​c.100G>T​(p.Ala34Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,642 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

EGF
NM_001963.6 missense

Scores

19

Clinical Significance

Not reported in ClinVar

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=0.044918478).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EGFNM_001963.6 linkc.100G>T p.Ala34Ser missense_variant Exon 1 of 24 ENST00000265171.10 NP_001954.2 P01133-1
EGFNM_001178130.3 linkc.100G>T p.Ala34Ser missense_variant Exon 1 of 23 NP_001171601.1 P01133-3
EGFNM_001178131.3 linkc.100G>T p.Ala34Ser missense_variant Exon 1 of 23 NP_001171602.1 P01133-2
EGFNM_001357021.2 linkc.100G>T p.Ala34Ser missense_variant Exon 1 of 20 NP_001343950.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EGFENST00000265171.10 linkc.100G>T p.Ala34Ser missense_variant Exon 1 of 24 1 NM_001963.6 ENSP00000265171.5 P01133-1
EGFENST00000503392.1 linkc.100G>T p.Ala34Ser missense_variant Exon 1 of 23 1 ENSP00000421384.1 P01133-3
EGFENST00000509793.5 linkc.100G>T p.Ala34Ser missense_variant Exon 1 of 23 2 ENSP00000424316.1 P01133-2
EGFENST00000652245.1 linkc.100G>T p.Ala34Ser missense_variant Exon 1 of 20 ENSP00000498337.1 A0A494C018

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152106
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249664
Hom.:
0
AF XY:
0.00000740
AC XY:
1
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:
0.00000891
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461536
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727056
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152106
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74296
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.078
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
0.027
DANN
Benign
0.49
DEOGEN2
Benign
0.28
.;T;.
Eigen
Benign
-1.8
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.033
N
LIST_S2
Benign
0.54
T;T;T
M_CAP
Benign
0.077
D
MetaRNN
Benign
0.045
T;T;T
MetaSVM
Benign
-0.71
T
MutationAssessor
Benign
-1.2
N;N;N
PrimateAI
Benign
0.20
T
PROVEAN
Benign
-0.050
N;N;N
REVEL
Benign
0.15
Sift
Benign
0.66
T;T;T
Sift4G
Benign
0.57
T;T;T
Polyphen
0.0040
B;B;.
Vest4
0.033
MutPred
0.45
Gain of disorder (P = 0.0155);Gain of disorder (P = 0.0155);Gain of disorder (P = 0.0155);
MVP
0.61
MPC
0.17
ClinPred
0.046
T
GERP RS
-4.3
Varity_R
0.032
gMVP
0.28

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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; API