4-109912994-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001963.6(EGF):c.-342C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00668 in 303,384 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (5 hom.)
• Consequence: EGF NM_001963.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0270

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 4-109912994-C-T is Benign according to our data. Variant chr4-109912994-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1317925.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.012 (1821/152312) while in subpopulation AFR AF= 0.0413 (1715/41562). AF 95% confidence interval is 0.0396. There are 29 homozygotes in gnomad4. There are 835 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGF	NM_001963.6	c.-342C>T		5_prime_UTR_variant	1/24	ENST00000265171.10
EGF	NM_001178130.3	c.-342C>T		5_prime_UTR_variant	1/23
EGF	NM_001178131.3	c.-342C>T		5_prime_UTR_variant	1/23
EGF	NM_001357021.2	c.-342C>T		5_prime_UTR_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGF	ENST00000265171.10	c.-342C>T		5_prime_UTR_variant	1/24	1	NM_001963.6	P1
EGF	ENST00000509793.5	c.-342C>T		5_prime_UTR_variant	1/23	2
EGF	ENST00000652245.1	c.-342C>T		5_prime_UTR_variant	1/20

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1808 AN: 152194 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00765

GnomAD4 exome AF: 0.00137 AC: 207 AN: 151072 Hom.: 5 Cov.: 0 AF XY: 0.00111 AC XY: 89 AN XY: 80476

Gnomad4 AFR exome AF: 0.0378

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000202

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000113

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.0120 AC: 1821 AN: 152312 Hom.: 29 Cov.: 32 AF XY: 0.0112 AC XY: 835 AN XY: 74482

Gnomad4 AFR AF: 0.0413

Gnomad4 AMR AF: 0.00542

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00201 Hom.: 6

Bravo AF: 0.0136

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 14, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	12
Dann	Benign	0.79

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: rs11568847; hg19: chr4-110834150;