chr4-109912912-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001963.6(EGF):​c.-424G>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 0.00639 in 188,554 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0077 ( 14 hom., cov: 33)
Exomes 𝑓: 0.00069 ( 0 hom. )

Consequence

EGF
NM_001963.6 5_prime_UTR

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.98
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 Benign. Variant got -14 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 4-109912912-G-A is Benign according to our data. Variant chr4-109912912-G-A is described in ClinVar as [Benign]. Clinvar id is 901088.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00774 (1179/152288) while in subpopulation AFR AF= 0.0268 (1114/41548). AF 95% confidence interval is 0.0255. There are 14 homozygotes in gnomad4. There are 531 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EGFNM_001963.6 linkuse as main transcriptc.-424G>A 5_prime_UTR_variant 1/24 ENST00000265171.10
EGFNM_001178130.3 linkuse as main transcriptc.-424G>A 5_prime_UTR_variant 1/23
EGFNM_001178131.3 linkuse as main transcriptc.-424G>A 5_prime_UTR_variant 1/23
EGFNM_001357021.2 linkuse as main transcriptc.-424G>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.-424G>A 5_prime_UTR_variant 1/241 NM_001963.6 P1P01133-1
EGFENST00000509793.5 linkuse as main transcriptc.-424G>A 5_prime_UTR_variant 1/232 P01133-2
EGFENST00000652245.1 linkuse as main transcriptc.-424G>A 5_prime_UTR_variant 1/20

Frequencies

GnomAD3 genomes
AF:
0.00774
AC:
1178
AN:
152170
Hom.:
14
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0269
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00282
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.00383
GnomAD4 exome
AF:
0.000689
AC:
25
AN:
36266
Hom.:
0
Cov.:
0
AF XY:
0.000760
AC XY:
14
AN XY:
18416
show subpopulations
Gnomad4 AFR exome
AF:
0.0168
Gnomad4 AMR exome
AF:
0.00190
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000471
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000458
Gnomad4 OTH exome
AF:
0.00202
GnomAD4 genome
AF:
0.00774
AC:
1179
AN:
152288
Hom.:
14
Cov.:
33
AF XY:
0.00713
AC XY:
531
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.0268
Gnomad4 AMR
AF:
0.00281
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00379
Alfa
AF:
0.00360
Hom.:
0
Bravo
AF:
0.00884
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

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

Submissions by phenotype

Renal hypomagnesemia 4 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
CADD
Benign
1.9
DANN
Benign
0.68

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

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

Other links and lift over

dbSNP: rs35397046; hg19: chr4-110834068; API