chr4-109980042-G-A

Position:

chr4-109980042-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.2124G>A(p.Met708Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 1,613,526 control chromosomes in the GnomAD database, including 154,549 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 0.52 ( 23704 hom., cov: 32)

Exomes 𝑓: 0.41 ( 130845 hom. )

Consequence

EGF
NM_001963.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.00300

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=1.4763177E-6).

BP6

Variant 4-109980042-G-A is Benign according to our data. Variant chr4-109980042-G-A is described in ClinVar as [Benign]. Clinvar id is 347245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-109980042-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.803 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.2124G>A	p.Met708Ile	missense_variant	14/24	ENST00000265171.10	NP_001954.2	P01133-1
EGF	NM_001178130.3 linkuse as main transcript	c.2124G>A	p.Met708Ile	missense_variant	14/23		NP_001171601.1	P01133-3
EGF	NM_001178131.3 linkuse as main transcript	c.1998G>A	p.Met666Ile	missense_variant	13/23		NP_001171602.1	P01133-2
EGF	NM_001357021.2 linkuse as main transcript	c.1998G>A	p.Met666Ile	missense_variant	13/20		NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
EGF	ENST00000265171.10 linkuse as main transcript	c.2124G>A	p.Met708Ile	missense_variant	14/24	1	NM_001963.6	ENSP00000265171.5	P01133-1
EGF	ENST00000503392.1 linkuse as main transcript	c.2124G>A	p.Met708Ile	missense_variant	14/23	1		ENSP00000421384.1	P01133-3
EGF	ENST00000509793.5 linkuse as main transcript	c.1998G>A	p.Met666Ile	missense_variant	13/23	2		ENSP00000424316.1	P01133-2
EGF	ENST00000652245.1 linkuse as main transcript	c.1998G>A	p.Met666Ile	missense_variant	13/20			ENSP00000498337.1	A0A494C018

Frequencies

GnomAD3 genomes

AF:

0.523

AC:

79537

AN:

151954

Hom.:

23630

Cov.:

show subpopulations

Gnomad AFR

AF:

0.810

Gnomad AMI

AF:

0.422

Gnomad AMR

AF:

0.517

Gnomad ASJ

AF:

0.462

Gnomad EAS

AF:

0.672

Gnomad SAS

AF:

0.480

Gnomad FIN

AF:

0.337

Gnomad MID

AF:

0.475

Gnomad NFE

AF:

0.377

Gnomad OTH

AF:

0.500

GnomAD3 exomes

AF:

0.464

AC:

116650

AN:

251148

Hom.:

29582

AF XY:

0.454

AC XY:

61599

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.824

Gnomad AMR exome

AF:

0.547

Gnomad ASJ exome

AF:

0.462

Gnomad EAS exome

AF:

0.684

Gnomad SAS exome

AF:

0.480

Gnomad FIN exome

AF:

0.332

Gnomad NFE exome

AF:

0.375

Gnomad OTH exome

AF:

0.439

GnomAD4 exome

AF:

0.413

AC:

603611

AN:

1461454

Hom.:

130845

Cov.:

AF XY:

0.413

AC XY:

299981

AN XY:

726994

show subpopulations

Gnomad4 AFR exome

AF:

0.829

Gnomad4 AMR exome

AF:

0.542

Gnomad4 ASJ exome

AF:

0.469

Gnomad4 EAS exome

AF:

0.687

Gnomad4 SAS exome

AF:

0.475

Gnomad4 FIN exome

AF:

0.338

Gnomad4 NFE exome

AF:

0.381

Gnomad4 OTH exome

AF:

0.452

GnomAD4 genome

AF:

0.524

AC:

79678

AN:

152072

Hom.:

23704

Cov.:

AF XY:

0.523

AC XY:

38880

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.810

Gnomad4 AMR

AF:

0.517

Gnomad4 ASJ

AF:

0.462

Gnomad4 EAS

AF:

0.673

Gnomad4 SAS

AF:

0.481

Gnomad4 FIN

AF:

0.337

Gnomad4 NFE

AF:

0.377

Gnomad4 OTH

AF:

0.504

Alfa

AF:

0.417

Hom.:

36243

Bravo

AF:

0.554

TwinsUK

AF:

0.380

AC:

1410

ALSPAC

AF:

0.389

AC:

1499

ESP6500AA

AF:

0.806

AC:

3553

ESP6500EA

AF:

0.381

AC:

3277

ExAC

AF:

0.466

AC:

56545

Asia WGS

AF:

0.590

AC:

2054

AN:

3478

EpiCase

AF:

0.391

EpiControl

AF:

0.388

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Renal hypomagnesemia 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

0.12

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.028

DANN

Benign

0.59

DEOGEN2

Benign

0.31

.;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.36

T;T;T

MetaRNN

Benign

0.0000015

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.6

.;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

0.20

N;N;N

REVEL

Benign

0.21

Sift

Benign

0.94

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.14

MutPred

0.31

.;Loss of disorder (P = 0.084);Loss of disorder (P = 0.084);

MPC

0.20

ClinPred

0.00058

GERP RS

1.5

Varity_R

0.061

gMVP

0.52

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