4-109952770-T-C

Variant names:

• chr4-109952770-T-C
• rs3796944
• NM_001963.6:c.941-6542T>C

Variant summary

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

The NM_001963.6(EGF):​c.941-6542T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 152,050 control chromosomes in the GnomAD database, including 25,374 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 0.55 (25374 hom., cov: 32)
• Consequence: EGF NM_001963.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0330
• Publications: 8 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.941-6542T>C		intron_variant	Intron 5 of 23	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.941-6542T>C		intron_variant	Intron 5 of 22		NP_001171601.1
EGF	NM_001178131.3	c.940+7495T>C		intron_variant	Intron 5 of 22		NP_001171602.1
EGF	NM_001357021.2	c.940+7495T>C		intron_variant	Intron 5 of 19		NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10	c.941-6542T>C		intron_variant	Intron 5 of 23	1	NM_001963.6	ENSP00000265171.5
EGF	ENST00000503392.1	c.941-6542T>C		intron_variant	Intron 5 of 22	1		ENSP00000421384.1
EGF	ENST00000509793.5	c.940+7495T>C		intron_variant	Intron 5 of 22	2		ENSP00000424316.1
EGF	ENST00000652245.1	c.940+7495T>C		intron_variant	Intron 5 of 19			ENSP00000498337.1

Frequencies

GnomAD3 genomes AF: 0.545 AC: 82752 AN: 151934 Hom.: 25305 Cov.: 32

Gnomad AFR AF: 0.828

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.489

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.500

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.531

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

GnomAD4 genome AF: 0.545 AC: 82879 AN: 152050 Hom.: 25374 Cov.: 32 AF XY: 0.543 AC XY: 40346 AN XY: 74340

African (AFR) AF: 0.828 AC: 34380 AN: 41518

American (AMR) AF: 0.534 AC: 8151 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.489 AC: 1694 AN: 3466

East Asian (EAS) AF: 0.694 AC: 3582 AN: 5162

South Asian (SAS) AF: 0.500 AC: 2411 AN: 4818

European-Finnish (FIN) AF: 0.353 AC: 3724 AN: 10554

Middle Eastern (MID) AF: 0.507 AC: 148 AN: 292

European-Non Finnish (NFE) AF: 0.401 AC: 27217 AN: 67954

Other (OTH) AF: 0.535 AC: 1128 AN: 2108

Alfa AF: 0.453 Hom.: 9439

Bravo AF: 0.575

Asia WGS AF: 0.608 AC: 2117 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.9
DANN	Benign	0.55
PhyloP100		-0.033
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: rs3796944; hg19: chr4-110873926;