4-109912994-C-T

Variant names:

• chr4-109912994-C-T
• rs11568847
• NM_001963.6:c.-342C>T

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.-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
• Publications: 2 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=-0.67).
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1821 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.-342C>T		5_prime_UTR_variant	Exon 1 of 24	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.-342C>T		5_prime_UTR_variant	Exon 1 of 23		NP_001171601.1
EGF	NM_001178131.3	c.-342C>T		5_prime_UTR_variant	Exon 1 of 23		NP_001171602.1
EGF	NM_001357021.2	c.-342C>T		5_prime_UTR_variant	Exon 1 of 20		NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10	c.-342C>T		5_prime_UTR_variant	Exon 1 of 24	1	NM_001963.6	ENSP00000265171.5
EGF	ENST00000509793.5	c.-342C>T		5_prime_UTR_variant	Exon 1 of 23	2		ENSP00000424316.1
EGF	ENST00000652245.1	c.-342C>T		5_prime_UTR_variant	Exon 1 of 20			ENSP00000498337.1
EGF	ENST00000503392.1	c.-342C>T		upstream_gene_variant		1		ENSP00000421384.1

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

African (AFR) AF: 0.0378 AC: 173 AN: 4578

American (AMR) AF: 0.00275 AC: 19 AN: 6900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3714

East Asian (EAS) AF: 0.00 AC: 0 AN: 7136

South Asian (SAS) AF: 0.000202 AC: 5 AN: 24736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7008

Middle Eastern (MID) AF: 0.00170 AC: 1 AN: 588

European-Non Finnish (NFE) AF: 0.0000113 AC: 1 AN: 88756

Other (OTH) AF: 0.00104 AC: 8 AN: 7656

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

African (AFR) AF: 0.0413 AC: 1715 AN: 41562

American (AMR) AF: 0.00542 AC: 83 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00458 Hom.: 12

Bravo AF: 0.0136

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 14, 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	-0.67
CADD	Benign	12
DANN	Benign	0.79
PhyloP100		-0.027
PromoterAI		0.026	Neutral
Mutation Taster		=300/0	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: rs11568847; hg19: chr4-110834150;