rs2237054

Variant names:

• chr4-109990033-T-A
• rs2237054
• NM_001963.6:c.2734+1324T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001963.6(EGF):​c.2734+1324T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 152,144 control chromosomes in the GnomAD database, including 4,220 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (4220 hom., cov: 32)
• Consequence: EGF NM_001963.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.869
• Publications: 9 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: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.2734+1324T>A		intron_variant	Intron 18 of 23	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.2734+1324T>A		intron_variant	Intron 18 of 22		NP_001171601.1
EGF	NM_001178131.3	c.2608+1324T>A		intron_variant	Intron 17 of 22		NP_001171602.1
EGF	NM_001357021.2	c.2366-3214T>A		intron_variant	Intron 15 of 19		NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10	c.2734+1324T>A		intron_variant	Intron 18 of 23	1	NM_001963.6	ENSP00000265171.5

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28052 AN: 152024 Hom.: 4199 Cov.: 32

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.0867

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.0486

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0672

Gnomad OTH AF: 0.163

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.185 AC: 28128 AN: 152144 Hom.: 4220 Cov.: 32 AF XY: 0.187 AC XY: 13917 AN XY: 74408

African (AFR) AF: 0.386 AC: 15991 AN: 41444

American (AMR) AF: 0.242 AC: 3704 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0867 AC: 301 AN: 3470

East Asian (EAS) AF: 0.365 AC: 1890 AN: 5180

South Asian (SAS) AF: 0.129 AC: 625 AN: 4830

European-Finnish (FIN) AF: 0.0486 AC: 516 AN: 10610

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0672 AC: 4569 AN: 68014

Other (OTH) AF: 0.166 AC: 350 AN: 2114

Alfa AF: 0.138 Hom.: 321

Bravo AF: 0.212

Asia WGS AF: 0.254 AC: 883 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.7
DANN	Benign	0.63
PhyloP100		0.87
Mutation Taster		=100/0	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: rs2237054; hg19: chr4-110911189;