chr4-109961965-G-A

Variant names:

• chr4-109961965-G-A
• rs11568943
• NM_001963.6:c.1292G>A

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:4
• Conservation: PhyloP100: -1.63
• Publications: 41 publications found

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 Gene-Disease associations (from GenCC):

• familial primary hypomagnesemia with normocalciuria and normocalcemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal hypomagnesemia 4

  Inheritance: Unknown, AR, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 347234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001963.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGF	NM_001963.6	MANE Select	c.1292G>A	p.Arg431Lys	missense	Exon 8 of 24	NP_001954.2	P01133-1
	EGF	NM_001178130.3		c.1292G>A	p.Arg431Lys	missense	Exon 8 of 23	NP_001171601.1	P01133-3
	EGF	NM_001178131.3		c.1166G>A	p.Arg389Lys	missense	Exon 7 of 23	NP_001171602.1	P01133-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGF	ENST00000265171.10	TSL:1 MANE Select	c.1292G>A	p.Arg431Lys	missense	Exon 8 of 24	ENSP00000265171.5	P01133-1
	EGF	ENST00000503392.1	TSL:1	c.1292G>A	p.Arg431Lys	missense	Exon 8 of 23	ENSP00000421384.1	P01133-3
	EGF	ENST00000868530.1		c.1292G>A	p.Arg431Lys	missense	Exon 8 of 24	ENSP00000538589.1

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

GnomAD2 exomes AF: 0.0982 AC: 24681 AN: 251258 AF XY: 0.0938

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 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

African (AFR) AF: 0.240 AC: 8026 AN: 33456

American (AMR) AF: 0.127 AC: 5680 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0863 AC: 2255 AN: 26122

East Asian (EAS) AF: 0.194 AC: 7688 AN: 39674

South Asian (SAS) AF: 0.0853 AC: 7355 AN: 86250

European-Finnish (FIN) AF: 0.0657 AC: 3509 AN: 53408

Middle Eastern (MID) AF: 0.114 AC: 655 AN: 5764

European-Non Finnish (NFE) AF: 0.0609 AC: 67731 AN: 1111730

Other (OTH) AF: 0.0866 AC: 5228 AN: 60370

GnomAD4 genome AF: 0.124 AC: 18845 AN: 152220 Hom.: 1628 Cov.: 33 AF XY: 0.124 AC XY: 9259 AN XY: 74440

African (AFR) AF: 0.237 AC: 9852 AN: 41502

American (AMR) AF: 0.117 AC: 1791 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0925 AC: 321 AN: 3470

East Asian (EAS) AF: 0.199 AC: 1032 AN: 5184

South Asian (SAS) AF: 0.0889 AC: 429 AN: 4826

European-Finnish (FIN) AF: 0.0564 AC: 598 AN: 10610

Middle Eastern (MID) AF: 0.0651 AC: 19 AN: 292

European-Non Finnish (NFE) AF: 0.0649 AC: 4411 AN: 68016

Other (OTH) AF: 0.117 AC: 246 AN: 2108

Alfa AF: 0.0873 Hom.: 3720

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Renal hypomagnesemia 4 (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.26	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.57	N
PhyloP100		-1.6
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.17
Sift	Benign	0.56	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.048
MPC		0.18
ClinPred		0.000025	T
GERP RS		-2.8
Varity_R		0.049
gMVP		0.34
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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