rs9992755

Variant names:

• chr4-109961434-A-G
• rs9992755
• NM_001963.6:c.1190-429A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-109961434-A-G
• chr4-109961434-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001963.6(EGF):​c.1190-429A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 152,024 control chromosomes in the GnomAD database, including 10,603 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.37 (10603 hom., cov: 32)
• Consequence: EGF NM_001963.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.98
• Publications: 19 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.1190-429A>G		intron_variant	Intron 7 of 23	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.1190-429A>G		intron_variant	Intron 7 of 22		NP_001171601.1
EGF	NM_001178131.3	c.1064-429A>G		intron_variant	Intron 6 of 22		NP_001171602.1
EGF	NM_001357021.2	c.1064-429A>G		intron_variant	Intron 6 of 19		NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10	c.1190-429A>G		intron_variant	Intron 7 of 23	1	NM_001963.6	ENSP00000265171.5

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55890 AN: 151906 Hom.: 10593 Cov.: 32

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.383

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.379

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.368 AC: 55939 AN: 152024 Hom.: 10603 Cov.: 32 AF XY: 0.364 AC XY: 27031 AN XY: 74312

African (AFR) AF: 0.449 AC: 18613 AN: 41436

American (AMR) AF: 0.400 AC: 6123 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 1331 AN: 3472

East Asian (EAS) AF: 0.267 AC: 1378 AN: 5152

South Asian (SAS) AF: 0.269 AC: 1296 AN: 4814

European-Finnish (FIN) AF: 0.309 AC: 3267 AN: 10566

Middle Eastern (MID) AF: 0.418 AC: 122 AN: 292

European-Non Finnish (NFE) AF: 0.334 AC: 22720 AN: 67980

Other (OTH) AF: 0.377 AC: 794 AN: 2108

Alfa AF: 0.348 Hom.: 39400

Bravo AF: 0.384

Asia WGS AF: 0.305 AC: 1065 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	8.3
DANN	Benign	0.67
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs9992755; hg19: chr4-110882590;