4-109913381-A-C

Position:

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):c.46A>C(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 (★★). 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: 𝑓 0.0032 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 33 hom. )

Consequence

EGF
NM_001963.6 missense

Scores

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]

EGF links:

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
EGF	NM_001963.6 linkuse as main transcript	c.46A>C	p.Ser16Arg	missense_variant	1/24	ENST00000265171.10
EGF	NM_001178130.3 linkuse as main transcript	c.46A>C	p.Ser16Arg	missense_variant	1/23
EGF	NM_001178131.3 linkuse as main transcript	c.46A>C	p.Ser16Arg	missense_variant	1/23
EGF	NM_001357021.2 linkuse as main transcript	c.46A>C	p.Ser16Arg	missense_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGF	ENST00000265171.10 linkuse as main transcript	c.46A>C	p.Ser16Arg	missense_variant	1/24	1	NM_001963.6	P1	P01133-1
EGF	ENST00000503392.1 linkuse as main transcript	c.46A>C	p.Ser16Arg	missense_variant	1/23	1			P01133-3
EGF	ENST00000509793.5 linkuse as main transcript	c.46A>C	p.Ser16Arg	missense_variant	1/23	2			P01133-2
EGF	ENST00000652245.1 linkuse as main transcript	c.46A>C	p.Ser16Arg	missense_variant	1/20

Frequencies

GnomAD3 genomes

AF:

0.00323

AC:

491

AN:

152144

Hom.:

Cov.:

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.:

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.:

Cov.:

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.:

Cov.:

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.:

Bravo

AF:

0.00125

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00404

AC:

490

Asia WGS

AF:

0.00866

AC:

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	See Variant Classification Assertion Criteria. -

Renal hypomagnesemia 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This 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

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

LIST_S2

Benign

0.79

T;T;T

MetaRNN

Benign

0.0047

T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Uncertain

2.1

M;M;M

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.30

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over