rs11568943

Positions:

chr4-109961965-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001963.6(EGF):c.1292G>A(p.Arg431Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0787 in 1,613,692 control chromosomes in the GnomAD database, including 6,673 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1628 hom., cov: 33)

Exomes 𝑓: 0.074 ( 5045 hom. )

Consequence

EGF
NM_001963.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.63

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:

EGF (HGNC:):

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=0.0027374923).

BP6

Variant 4-109961965-G-A is Benign according to our data. Variant chr4-109961965-G-A is described in ClinVar as [Benign]. Clinvar id is 347234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-109961965-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGF	NM_001963.6 linkuse as main transcript	c.1292G>A	p.Arg431Lys	missense_variant	8/24	ENST00000265171.10	NP_001954.2	P01133-1
EGF	NM_001178130.3 linkuse as main transcript	c.1292G>A	p.Arg431Lys	missense_variant	8/23		NP_001171601.1	P01133-3
EGF	NM_001178131.3 linkuse as main transcript	c.1166G>A	p.Arg389Lys	missense_variant	7/23		NP_001171602.1	P01133-2
EGF	NM_001357021.2 linkuse as main transcript	c.1166G>A	p.Arg389Lys	missense_variant	7/20		NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10 linkuse as main transcript	c.1292G>A	p.Arg431Lys	missense_variant	8/24	1	NM_001963.6	ENSP00000265171.5		P01133-1

Frequencies

GnomAD3 genomes

AF:

0.124

AC:

18801

AN:

152104

Hom.:

1620

Cov.:

show subpopulations

Gnomad AFR

AF:

0.237

Gnomad AMI

AF:

0.161

Gnomad AMR

AF:

0.117

Gnomad ASJ

AF:

0.0925

Gnomad EAS

AF:

0.200

Gnomad SAS

AF:

0.0886

Gnomad FIN

AF:

0.0564

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0648

Gnomad OTH

AF:

0.114

GnomAD3 exomes

AF:

0.0982

AC:

24681

AN:

251258

Hom.:

1572

AF XY:

0.0938

AC XY:

12733

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.240

Gnomad AMR exome

AF:

0.131

Gnomad ASJ exome

AF:

0.0861

Gnomad EAS exome

AF:

0.190

Gnomad SAS exome

AF:

0.0872

Gnomad FIN exome

AF:

0.0637

Gnomad NFE exome

AF:

0.0640

Gnomad OTH exome

AF:

0.0945

GnomAD4 exome

AF:

0.0740

AC:

108127

AN:

1461472

Hom.:

5045

Cov.:

AF XY:

0.0739

AC XY:

53693

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.240

Gnomad4 AMR exome

AF:

0.127

Gnomad4 ASJ exome

AF:

0.0863

Gnomad4 EAS exome

AF:

0.194

Gnomad4 SAS exome

AF:

0.0853

Gnomad4 FIN exome

AF:

0.0657

Gnomad4 NFE exome

AF:

0.0609

Gnomad4 OTH exome

AF:

0.0866

GnomAD4 genome

AF:

0.124

AC:

18845

AN:

152220

Hom.:

1628

Cov.:

AF XY:

0.124

AC XY:

9259

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.237

Gnomad4 AMR

AF:

0.117

Gnomad4 ASJ

AF:

0.0925

Gnomad4 EAS

AF:

0.199

Gnomad4 SAS

AF:

0.0889

Gnomad4 FIN

AF:

0.0564

Gnomad4 NFE

AF:

0.0649

Gnomad4 OTH

AF:

0.117

Alfa

AF:

0.0813

Hom.:

1551

Bravo

AF:

0.132

TwinsUK

AF:

0.0618

AC:

229

ALSPAC

AF:

0.0573

AC:

221

ESP6500AA

AF:

0.235

AC:

1035

ESP6500EA

AF:

0.0669

AC:

575

ExAC

AF:

0.0984

AC:

11951

Asia WGS

AF:

0.147

AC:

514

AN:

3478

EpiCase

AF:

0.0671

EpiControl

AF:

0.0673

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign

0.066

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

4.3

DANN

Benign

0.56

DEOGEN2

Benign

0.26

.;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.19

T;T;T

MetaRNN

Benign

0.0027

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.57

.;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

0.040

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.56

T;T;T

Sift4G

Benign

0.70

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.048

MPC

0.18

ClinPred

0.000025

GERP RS

-2.8

Varity_R

0.049

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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