chr4-109912889-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001963.6(EGF):​c.-447G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000776 in 179,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00081 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00056 ( 0 hom. )

Consequence

EGF
NM_001963.6 5_prime_UTR

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.31
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.57).
BP6
Variant 4-109912889-G-A is Benign according to our data. Variant chr4-109912889-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 347218.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EGFNM_001963.6 linkuse as main transcriptc.-447G>A 5_prime_UTR_variant 1/24 ENST00000265171.10
EGFNM_001178130.3 linkuse as main transcriptc.-447G>A 5_prime_UTR_variant 1/23
EGFNM_001178131.3 linkuse as main transcriptc.-447G>A 5_prime_UTR_variant 1/23
EGFNM_001357021.2 linkuse as main transcriptc.-447G>A 5_prime_UTR_variant 1/20

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EGFENST00000265171.10 linkuse as main transcriptc.-447G>A 5_prime_UTR_variant 1/241 NM_001963.6 P1P01133-1
EGFENST00000509793.5 linkuse as main transcriptc.-447G>A 5_prime_UTR_variant 1/232 P01133-2
EGFENST00000652245.1 linkuse as main transcriptc.-447G>A 5_prime_UTR_variant 1/20

Frequencies

GnomAD3 genomes
AF:
0.000821
AC:
125
AN:
152202
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000796
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00295
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000603
Gnomad OTH
AF:
0.00143
GnomAD4 exome
AF:
0.000560
AC:
15
AN:
26766
Hom.:
0
Cov.:
0
AF XY:
0.000444
AC XY:
6
AN XY:
13510
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00204
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000436
Gnomad4 OTH exome
AF:
0.00139
GnomAD4 genome
AF:
0.000814
AC:
124
AN:
152320
Hom.:
0
Cov.:
33
AF XY:
0.000846
AC XY:
63
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.000770
Gnomad4 AMR
AF:
0.00294
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000603
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000971
Hom.:
0
Bravo
AF:
0.00121

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Renal hypomagnesemia 4 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.57
CADD
Benign
16
DANN
Benign
0.88

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs56399752; hg19: chr4-110834045; API