4-109913234-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001963.6(EGF):c.-102G>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 0.00141 in 1,496,942 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: EGF NM_001963.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.879

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-109913234-G-A is Benign according to our data. Variant chr4-109913234-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 347223.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGF	NM_001963.6	c.-102G>A		5_prime_UTR_variant	1/24	ENST00000265171.10
EGF	NM_001178130.3	c.-102G>A		5_prime_UTR_variant	1/23
EGF	NM_001178131.3	c.-102G>A		5_prime_UTR_variant	1/23
EGF	NM_001357021.2	c.-102G>A		5_prime_UTR_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGF	ENST00000265171.10	c.-102G>A		5_prime_UTR_variant	1/24	1	NM_001963.6	P1
EGF	ENST00000509793.5	c.-102G>A		5_prime_UTR_variant	1/23	2
EGF	ENST00000652245.1	c.-102G>A		5_prime_UTR_variant	1/20
EGF	ENST00000503392.1			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00145 AC: 1949 AN: 1344644 Hom.: 4 Cov.: 19 AF XY: 0.00149 AC XY: 1006 AN XY: 675162

Gnomad4 AFR exome AF: 0.000161

Gnomad4 AMR exome AF: 0.000409

Gnomad4 ASJ exome AF: 0.000480

Gnomad4 EAS exome AF: 0.0000262

Gnomad4 SAS exome AF: 0.00151

Gnomad4 FIN exome AF: 0.000105

Gnomad4 NFE exome AF: 0.00168

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000913 AC XY: 68 AN XY: 74468

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00176

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000443 Hom.: 0

Bravo AF: 0.00108

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal hypomagnesemia 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This 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	-0.87
Cadd	Benign	9.3
Dann	Benign	0.61

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

Other links and lift over

dbSNP: rs11568848; hg19: chr4-110834390; COSMIC: COSV54486216; COSMIC: COSV54486216;