rs11568943

chr4-109961965-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.63

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]

ACMG classification

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	UniProt
EGF	NM_001963.6	c.1292G>A	p.Arg431Lys	missense_variant	8/24	ENST00000265171.10
EGF	NM_001178130.3	c.1292G>A	p.Arg431Lys	missense_variant	8/23
EGF	NM_001178131.3	c.1166G>A	p.Arg389Lys	missense_variant	7/23
EGF	NM_001357021.2	c.1166G>A	p.Arg389Lys	missense_variant	7/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGF	ENST00000265171.10	c.1292G>A	p.Arg431Lys	missense_variant	8/24	1	NM_001963.6	P1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18801 AN: 152104 Hom.: 1620 Cov.: 33

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

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.: 32 AF XY: 0.0739 AC XY: 53693 AN XY: 727048

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.: 33 AF XY: 0.124 AC XY: 9259 AN XY: 74440

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

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	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	4.3
Dann	Benign	0.56
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.19	T;T;T
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.26	T
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	T
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

Other links and lift over

dbSNP: rs11568943; hg19: chr4-110883121; COSMIC: COSV54479381;