rs2250616

Positions:

• chr4-109915408-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001963.6(EGF):​c.127+1946G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 151,938 control chromosomes in the GnomAD database, including 6,692 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 0.29 (6692 hom., cov: 32)
• Consequence: EGF NM_001963.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.519

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGF	NM_001963.6	c.127+1946G>A		intron_variant		ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.127+1946G>A		intron_variant			NP_001171601.1
EGF	NM_001178131.3	c.127+1946G>A		intron_variant			NP_001171602.1
EGF	NM_001357021.2	c.127+1946G>A		intron_variant			NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10	c.127+1946G>A		intron_variant		1	NM_001963.6	ENSP00000265171	P1
EGF	ENST00000503392.1	c.127+1946G>A		intron_variant		1		ENSP00000421384
EGF	ENST00000509793.5	c.127+1946G>A		intron_variant		2		ENSP00000424316
EGF	ENST00000652245.1	c.127+1946G>A		intron_variant				ENSP00000498337

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43882 AN: 151820 Hom.: 6692 Cov.: 32

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.0843

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.311

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

GnomAD4 genome AF: 0.289 AC: 43896 AN: 151938 Hom.: 6692 Cov.: 32 AF XY: 0.283 AC XY: 20999 AN XY: 74244

Gnomad4 AFR AF: 0.251

Gnomad4 AMR AF: 0.261

Gnomad4 ASJ AF: 0.381

Gnomad4 EAS AF: 0.0849

Gnomad4 SAS AF: 0.222

Gnomad4 FIN AF: 0.300

Gnomad4 NFE AF: 0.330

Gnomad4 OTH AF: 0.308

Alfa AF: 0.314 Hom.: 1284

Bravo AF: 0.287

Asia WGS AF: 0.159 AC: 557 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.0
DANN	Benign	0.75

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: rs2250616; hg19: chr4-110836564;