4-109983292-C-T

Variant names:

• chr4-109983292-C-T
• rs6824594
• NM_001963.6:c.2372-130C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001963.6(EGF):​c.2372-130C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 1,087,190 control chromosomes in the GnomAD database, including 111,869 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.52 (23705 hom., cov: 32)
  • Exomes 𝑓: 0.42 (88164 hom.)
• Consequence: EGF NM_001963.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.712

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 4-109983292-C-T is Benign according to our data. Variant chr4-109983292-C-T is described in ClinVar as [Benign]. Clinvar id is 1250332.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.2372-130C>T		intron_variant	Intron 15 of 23	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.2372-130C>T		intron_variant	Intron 15 of 22		NP_001171601.1
EGF	NM_001178131.3	c.2246-130C>T		intron_variant	Intron 14 of 22		NP_001171602.1
EGF	NM_001357021.2	c.2246-130C>T		intron_variant	Intron 14 of 19		NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10	c.2372-130C>T		intron_variant	Intron 15 of 23	1	NM_001963.6	ENSP00000265171.5

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79539 AN: 151942 Hom.: 23631 Cov.: 32

Gnomad AFR AF: 0.810

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.500

GnomAD4 exome AF: 0.423 AC: 395838 AN: 935130 Hom.: 88164 AF XY: 0.423 AC XY: 202229 AN XY: 478304

Gnomad4 AFR exome AF: 0.828 AC: 18611 AN: 22482

Gnomad4 AMR exome AF: 0.536 AC: 17863 AN: 33328

Gnomad4 ASJ exome AF: 0.471 AC: 9859 AN: 20914

Gnomad4 EAS exome AF: 0.684 AC: 22078 AN: 32258

Gnomad4 SAS exome AF: 0.473 AC: 31848 AN: 67288

Gnomad4 FIN exome AF: 0.342 AC: 12509 AN: 36570

Gnomad4 NFE exome AF: 0.387 AC: 262111 AN: 676788

Gnomad4 Remaining exome AF: 0.461 AC: 19436 AN: 42122

GnomAD4 genome AF: 0.524 AC: 79680 AN: 152060 Hom.: 23705 Cov.: 32 AF XY: 0.523 AC XY: 38884 AN XY: 74338

Gnomad4 AFR AF: 0.810 AC: 0.810084 AN: 0.810084

Gnomad4 AMR AF: 0.517 AC: 0.517359 AN: 0.517359

Gnomad4 ASJ AF: 0.462 AC: 0.462493 AN: 0.462493

Gnomad4 EAS AF: 0.671 AC: 0.671175 AN: 0.671175

Gnomad4 SAS AF: 0.480 AC: 0.479668 AN: 0.479668

Gnomad4 FIN AF: 0.337 AC: 0.337152 AN: 0.337152

Gnomad4 NFE AF: 0.377 AC: 0.377134 AN: 0.377134

Gnomad4 OTH AF: 0.504 AC: 0.504257 AN: 0.504257

Alfa AF: 0.456 Hom.: 4393

Bravo AF: 0.554

Asia WGS AF: 0.589 AC: 2050 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: 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	-0.89
CADD	Benign	0.81
DANN	Benign	0.48
Mutation Taster		=100/0	polymorphism (auto)

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: rs6824594; hg19: chr4-110904448;