rs1860129

Variant names:

• chr4-109965187-G-C
• rs1860129
• NM_001963.6:c.1575+650G>C

Variant summary

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

The NM_001963.6(EGF):​c.1575+650G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 151,924 control chromosomes in the GnomAD database, including 25,315 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 0.54 (25315 hom., cov: 32)
• Consequence: EGF NM_001963.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.391
• 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.1575+650G>C		intron_variant	Intron 10 of 23	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.1575+650G>C		intron_variant	Intron 10 of 22		NP_001171601.1
EGF	NM_001178131.3	c.1449+650G>C		intron_variant	Intron 9 of 22		NP_001171602.1
EGF	NM_001357021.2	c.1449+650G>C		intron_variant	Intron 9 of 19		NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10	c.1575+650G>C		intron_variant	Intron 10 of 23	1	NM_001963.6	ENSP00000265171.5
EGF	ENST00000503392.1	c.1575+650G>C		intron_variant	Intron 10 of 22	1		ENSP00000421384.1
EGF	ENST00000509793.5	c.1449+650G>C		intron_variant	Intron 9 of 22	2		ENSP00000424316.1
EGF	ENST00000652245.1	c.1449+650G>C		intron_variant	Intron 9 of 19			ENSP00000498337.1

Frequencies

GnomAD3 genomes AF: 0.544 AC: 82600 AN: 151806 Hom.: 25247 Cov.: 32

Gnomad AFR AF: 0.828

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.538

Gnomad ASJ AF: 0.485

Gnomad EAS AF: 0.699

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.531

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

GnomAD4 genome AF: 0.545 AC: 82727 AN: 151924 Hom.: 25315 Cov.: 32 AF XY: 0.542 AC XY: 40259 AN XY: 74244

African (AFR) AF: 0.829 AC: 34402 AN: 41504

American (AMR) AF: 0.538 AC: 8208 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.485 AC: 1679 AN: 3460

East Asian (EAS) AF: 0.700 AC: 3617 AN: 5164

South Asian (SAS) AF: 0.445 AC: 2141 AN: 4816

European-Finnish (FIN) AF: 0.367 AC: 3859 AN: 10526

Middle Eastern (MID) AF: 0.493 AC: 144 AN: 292

European-Non Finnish (NFE) AF: 0.399 AC: 27102 AN: 67882

Other (OTH) AF: 0.536 AC: 1131 AN: 2112

Alfa AF: 0.492 Hom.: 2579

Bravo AF: 0.575

Asia WGS AF: 0.604 AC: 2099 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	12
DANN	Benign	0.65
PhyloP100		-0.39
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: rs1860129; hg19: chr4-110886343;