rs11568995

Variant names:

• chr4-109976429-G-A
• rs11568995
• NM_001963.6:c.2053+194G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001963.6(EGF):​c.2053+194G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.027 in 152,202 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.027 (76 hom., cov: 32)
• Consequence: EGF NM_001963.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.875
• Publications: 7 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=-0.89).
• BP6: Variant 4-109976429-G-A is Benign according to our data. Variant chr4-109976429-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1317865.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.027 (4111/152202) while in subpopulation AFR AF = 0.045 (1869/41534). AF 95% confidence interval is 0.0433. There are 76 homozygotes in GnomAd4. There are 2000 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4111 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.2053+194G>A		intron_variant	Intron 13 of 23	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.2053+194G>A		intron_variant	Intron 13 of 22		NP_001171601.1
EGF	NM_001178131.3	c.1927+194G>A		intron_variant	Intron 12 of 22		NP_001171602.1
EGF	NM_001357021.2	c.1927+194G>A		intron_variant	Intron 12 of 19		NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10	c.2053+194G>A		intron_variant	Intron 13 of 23	1	NM_001963.6	ENSP00000265171.5

Frequencies

GnomAD3 genomes AF: 0.0270 AC: 4107 AN: 152084 Hom.: 76 Cov.: 32

Gnomad AFR AF: 0.0450

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0330

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0227

Gnomad OTH AF: 0.0196

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

GnomAD4 genome AF: 0.0270 AC: 4111 AN: 152202 Hom.: 76 Cov.: 32 AF XY: 0.0269 AC XY: 2000 AN XY: 74416

African (AFR) AF: 0.0450 AC: 1869 AN: 41534

American (AMR) AF: 0.0117 AC: 179 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 26 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4824

European-Finnish (FIN) AF: 0.0330 AC: 350 AN: 10594

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0227 AC: 1544 AN: 68000

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.0237 Hom.: 82

Bravo AF: 0.0269

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 03, 2020

GeneDx

Significance: Likely 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	-0.89
CADD	Benign	0.67
DANN	Benign	0.77
PhyloP100		-0.88
Mutation Taster		=100/0	polymorphism

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: rs11568995; hg19: chr4-110897585;