rs11569126

Variant names:

• chr4-110008497-G-A
• rs11569126
• NM_001963.6:c.3370+267G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001963.6(EGF):​c.3370+267G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0482 in 152,218 control chromosomes in the GnomAD database, including 314 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.048 (314 hom., cov: 32)
• Consequence: EGF NM_001963.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.544
• Publications: 6 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 4-110008497-G-A is Benign according to our data. Variant chr4-110008497-G-A is described in ClinVar as Benign. ClinVar VariationId is 1268903.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.3370+267G>A		intron_variant	Intron 23 of 23	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.3247+267G>A		intron_variant	Intron 22 of 22		NP_001171601.1
EGF	NM_001178131.3	c.3244+267G>A		intron_variant	Intron 22 of 22		NP_001171602.1
EGF	NM_001357021.2	c.2923-2705G>A		intron_variant	Intron 19 of 19		NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10	c.3370+267G>A		intron_variant	Intron 23 of 23	1	NM_001963.6	ENSP00000265171.5

Frequencies

GnomAD3 genomes AF: 0.0482 AC: 7334 AN: 152100 Hom.: 313 Cov.: 32

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.0662

Gnomad ASJ AF: 0.0723

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.0644

Gnomad FIN AF: 0.0441

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0531

Gnomad OTH AF: 0.0531

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

GnomAD4 genome AF: 0.0482 AC: 7341 AN: 152218 Hom.: 314 Cov.: 32 AF XY: 0.0500 AC XY: 3725 AN XY: 74440

African (AFR) AF: 0.0127 AC: 529 AN: 41560

American (AMR) AF: 0.0662 AC: 1012 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0723 AC: 251 AN: 3470

East Asian (EAS) AF: 0.169 AC: 872 AN: 5160

South Asian (SAS) AF: 0.0648 AC: 312 AN: 4812

European-Finnish (FIN) AF: 0.0441 AC: 468 AN: 10604

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0531 AC: 3612 AN: 68002

Other (OTH) AF: 0.0558 AC: 118 AN: 2114

Alfa AF: 0.0540 Hom.: 335

Bravo AF: 0.0475

Asia WGS AF: 0.103 AC: 359 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 03, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.1
DANN	Benign	0.56
PhyloP100		0.54
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: rs11569126; hg19: chr4-110929653;