4-109976379-G-A

Position:

• chr4-109976379-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001963.6(EGF):​c.2053+144G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 767,714 control chromosomes in the GnomAD database, including 35,445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (6419 hom., cov: 33)
  • Exomes 𝑓: 0.30 (29026 hom.)
• Consequence: EGF NM_001963.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.360

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=-0.83).
• BP6: Variant 4-109976379-G-A is Benign according to our data. Variant chr4-109976379-G-A is described in ClinVar as [Benign]. Clinvar id is 1266495.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGF	NM_001963.6	c.2053+144G>A		intron_variant		ENST00000265171.10
EGF	NM_001178130.3	c.2053+144G>A		intron_variant
EGF	NM_001178131.3	c.1927+144G>A		intron_variant
EGF	NM_001357021.2	c.1927+144G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGF	ENST00000265171.10	c.2053+144G>A		intron_variant		1	NM_001963.6	P1

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42792 AN: 151976 Hom.: 6418 Cov.: 33

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.0807

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.301

GnomAD4 exome AF: 0.297 AC: 183002 AN: 615620 Hom.: 29026 AF XY: 0.295 AC XY: 96347 AN XY: 326320

Gnomad4 AFR exome AF: 0.227

Gnomad4 AMR exome AF: 0.227

Gnomad4 ASJ exome AF: 0.382

Gnomad4 EAS exome AF: 0.0896

Gnomad4 SAS exome AF: 0.225

Gnomad4 FIN exome AF: 0.288

Gnomad4 NFE exome AF: 0.332

Gnomad4 OTH exome AF: 0.313

GnomAD4 genome AF: 0.281 AC: 42813 AN: 152094 Hom.: 6419 Cov.: 33 AF XY: 0.277 AC XY: 20613 AN XY: 74374

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.260

Gnomad4 ASJ AF: 0.368

Gnomad4 EAS AF: 0.0813

Gnomad4 SAS AF: 0.216

Gnomad4 FIN AF: 0.297

Gnomad4 NFE AF: 0.328

Gnomad4 OTH AF: 0.298

Alfa AF: 0.323 Hom.: 10509

Bravo AF: 0.278

Asia WGS AF: 0.167 AC: 583 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.71
DANN	Benign	0.69

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: rs11568994; hg19: chr4-110897535;