chr4-109913381-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001963.6(EGF):ā€‹c.46A>Cā€‹(p.Ser16Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,613,952 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S16T) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.0032 ( 7 hom., cov: 32)
Exomes š‘“: 0.0018 ( 33 hom. )

Consequence

EGF
NM_001963.6 missense

Scores

5
13

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.423
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0047091246).
BP6
Variant 4-109913381-A-C is Benign according to our data. Variant chr4-109913381-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 347224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00323 (492/152262) while in subpopulation EAS AF= 0.0257 (133/5176). AF 95% confidence interval is 0.0221. There are 7 homozygotes in gnomad4. There are 336 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EGFNM_001963.6 linkuse as main transcriptc.46A>C p.Ser16Arg missense_variant 1/24 ENST00000265171.10
EGFNM_001178130.3 linkuse as main transcriptc.46A>C p.Ser16Arg missense_variant 1/23
EGFNM_001178131.3 linkuse as main transcriptc.46A>C p.Ser16Arg missense_variant 1/23
EGFNM_001357021.2 linkuse as main transcriptc.46A>C p.Ser16Arg missense_variant 1/20

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EGFENST00000265171.10 linkuse as main transcriptc.46A>C p.Ser16Arg missense_variant 1/241 NM_001963.6 P1P01133-1
EGFENST00000503392.1 linkuse as main transcriptc.46A>C p.Ser16Arg missense_variant 1/231 P01133-3
EGFENST00000509793.5 linkuse as main transcriptc.46A>C p.Ser16Arg missense_variant 1/232 P01133-2
EGFENST00000652245.1 linkuse as main transcriptc.46A>C p.Ser16Arg missense_variant 1/20

Frequencies

GnomAD3 genomes
AF:
0.00323
AC:
491
AN:
152144
Hom.:
7
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.0254
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.0276
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000720
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.00450
AC:
1131
AN:
251146
Hom.:
16
AF XY:
0.00430
AC XY:
584
AN XY:
135754
show subpopulations
Gnomad AFR exome
AF:
0.000246
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.000595
Gnomad EAS exome
AF:
0.0264
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.0250
Gnomad NFE exome
AF:
0.000555
Gnomad OTH exome
AF:
0.00489
GnomAD4 exome
AF:
0.00178
AC:
2606
AN:
1461690
Hom.:
33
Cov.:
31
AF XY:
0.00169
AC XY:
1226
AN XY:
727150
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.0000448
Gnomad4 ASJ exome
AF:
0.000459
Gnomad4 EAS exome
AF:
0.0277
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.0230
Gnomad4 NFE exome
AF:
0.000138
Gnomad4 OTH exome
AF:
0.00164
GnomAD4 genome
AF:
0.00323
AC:
492
AN:
152262
Hom.:
7
Cov.:
32
AF XY:
0.00451
AC XY:
336
AN XY:
74446
show subpopulations
Gnomad4 AFR
AF:
0.000192
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.0257
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.0276
Gnomad4 NFE
AF:
0.000720
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.00102
Hom.:
10
Bravo
AF:
0.00125
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.00404
AC:
490
Asia WGS
AF:
0.00866
AC:
30
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 04, 2021See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitterclinical testingInvitaeJan 20, 2024- -
Renal hypomagnesemia 4 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
6.2
DANN
Benign
0.93
DEOGEN2
Uncertain
0.48
.;T;.
Eigen
Benign
-0.82
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.10
N
LIST_S2
Benign
0.79
T;T;T
MetaRNN
Benign
0.0047
T;T;T
MetaSVM
Benign
-0.33
T
MutationAssessor
Uncertain
2.1
M;M;M
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-1.9
N;N;N
REVEL
Uncertain
0.40
Sift
Uncertain
0.015
D;D;D
Sift4G
Benign
0.061
T;T;T
Polyphen
0.96
D;P;.
Vest4
0.23
MutPred
0.57
Loss of ubiquitination at K14 (P = 0.0524);Loss of ubiquitination at K14 (P = 0.0524);Loss of ubiquitination at K14 (P = 0.0524);
MVP
0.86
MPC
0.58
ClinPred
0.018
T
GERP RS
-5.5
Varity_R
0.12
gMVP
0.48

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs11568849; hg19: chr4-110834537; COSMIC: COSV99490525; API