rs2237051

Variant names:

• chr4-109980042-G-A
• rs2237051
• NM_001963.6:c.2124G>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.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. 16/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.00300
• Publications: 74 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=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 VariationId is 347245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.803 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.2124G>A	p.Met708Ile	missense	Exon 14 of 24	NP_001954.2	P01133-1
	EGF	NM_001178130.3		c.2124G>A	p.Met708Ile	missense	Exon 14 of 23	NP_001171601.1	P01133-3
	EGF	NM_001178131.3		c.1998G>A	p.Met666Ile	missense	Exon 13 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.2124G>A	p.Met708Ile	missense	Exon 14 of 24	ENSP00000265171.5	P01133-1
	EGF	ENST00000503392.1	TSL:1	c.2124G>A	p.Met708Ile	missense	Exon 14 of 23	ENSP00000421384.1	P01133-3
	EGF	ENST00000868530.1		c.2124G>A	p.Met708Ile	missense	Exon 14 of 24	ENSP00000538589.1

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79537 AN: 151954 Hom.: 23630 Cov.: 32

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

GnomAD2 exomes AF: 0.464 AC: 116650 AN: 251148 AF XY: 0.454

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 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.: 41 AF XY: 0.413 AC XY: 299981 AN XY: 726994

African (AFR) AF: 0.829 AC: 27753 AN: 33462

American (AMR) AF: 0.542 AC: 24227 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 12254 AN: 26130

East Asian (EAS) AF: 0.687 AC: 27252 AN: 39692

South Asian (SAS) AF: 0.475 AC: 40947 AN: 86202

European-Finnish (FIN) AF: 0.338 AC: 18061 AN: 53402

Middle Eastern (MID) AF: 0.439 AC: 2531 AN: 5762

European-Non Finnish (NFE) AF: 0.381 AC: 423294 AN: 1111722

Other (OTH) AF: 0.452 AC: 27292 AN: 60386

GnomAD4 genome AF: 0.524 AC: 79678 AN: 152072 Hom.: 23704 Cov.: 32 AF XY: 0.523 AC XY: 38880 AN XY: 74336

African (AFR) AF: 0.810 AC: 33609 AN: 41488

American (AMR) AF: 0.517 AC: 7895 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1603 AN: 3470

East Asian (EAS) AF: 0.673 AC: 3480 AN: 5172

South Asian (SAS) AF: 0.481 AC: 2319 AN: 4824

European-Finnish (FIN) AF: 0.337 AC: 3558 AN: 10558

Middle Eastern (MID) AF: 0.479 AC: 140 AN: 292

European-Non Finnish (NFE) AF: 0.377 AC: 25625 AN: 67976

Other (OTH) AF: 0.504 AC: 1065 AN: 2112

Alfa AF: 0.432 Hom.: 77494

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Renal hypomagnesemia 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.56	T
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	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.6	N
PhyloP100		-0.0030
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.21
Sift	Benign	0.94	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.31		Loss of disorder (P = 0.084)
MPC		0.20
ClinPred		0.00058	T
GERP RS		1.5
Varity_R		0.061
gMVP		0.52
Mutation Taster		=99/1	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: rs2237051; hg19: chr4-110901198; COSMIC: COSV54478936; COSMIC: COSV54478936;