NM_001963.6:c.2053+144G>A

Variant names:

• chr4-109976379-G-A
• rs11568994
• NM_001963.6:c.2053+144G>A

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.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
• Publications: 11 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=-0.83).
• BP6: Variant 4-109976379-G-A is Benign according to our data. Variant chr4-109976379-G-A is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.2053+144G>A		intron_variant	Intron 13 of 23	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.2053+144G>A		intron_variant	Intron 13 of 22		NP_001171601.1
EGF	NM_001178131.3	c.1927+144G>A		intron_variant	Intron 12 of 22		NP_001171602.1
EGF	NM_001357021.2	c.1927+144G>A		intron_variant	Intron 12 of 19		NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10	c.2053+144G>A		intron_variant	Intron 13 of 23	1	NM_001963.6	ENSP00000265171.5

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

African (AFR) AF: 0.227 AC: 3769 AN: 16596

American (AMR) AF: 0.227 AC: 7746 AN: 34098

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 7602 AN: 19888

East Asian (EAS) AF: 0.0896 AC: 2874 AN: 32080

South Asian (SAS) AF: 0.225 AC: 14051 AN: 62312

European-Finnish (FIN) AF: 0.288 AC: 12708 AN: 44116

Middle Eastern (MID) AF: 0.327 AC: 833 AN: 2544

European-Non Finnish (NFE) AF: 0.332 AC: 123333 AN: 371812

Other (OTH) AF: 0.313 AC: 10086 AN: 32174

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

African (AFR) AF: 0.232 AC: 9619 AN: 41482

American (AMR) AF: 0.260 AC: 3975 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1278 AN: 3470

East Asian (EAS) AF: 0.0813 AC: 422 AN: 5190

South Asian (SAS) AF: 0.216 AC: 1041 AN: 4818

European-Finnish (FIN) AF: 0.297 AC: 3144 AN: 10570

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.328 AC: 22324 AN: 67970

Other (OTH) AF: 0.298 AC: 630 AN: 2112

Alfa AF: 0.319 Hom.: 13136

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

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	-0.83
CADD	Benign	0.71
DANN	Benign	0.69
PhyloP100		-0.36
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

Other links and lift over

dbSNP: rs11568994; hg19: chr4-110897535;