rs971696

Variant names:

• chr4-110006709-A-T
• rs971696
• NM_001963.6:c.3292-1443A>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.3292-1443A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 152,146 control chromosomes in the GnomAD database, including 10,635 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 0.27 (10635 hom., cov: 33)
• Consequence: EGF NM_001963.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0920
• Publications: 6 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.3292-1443A>T		intron_variant	Intron 22 of 23	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.3169-1443A>T		intron_variant	Intron 21 of 22		NP_001171601.1
EGF	NM_001178131.3	c.3166-1443A>T		intron_variant	Intron 21 of 22		NP_001171602.1
EGF	NM_001357021.2	c.2922+2087A>T		intron_variant	Intron 19 of 19		NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10	c.3292-1443A>T		intron_variant	Intron 22 of 23	1	NM_001963.6	ENSP00000265171.5

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40900 AN: 152028 Hom.: 10569 Cov.: 33

Gnomad AFR AF: 0.640

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.0860

Gnomad EAS AF: 0.583

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.0524

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0660

Gnomad OTH AF: 0.217

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

GnomAD4 genome AF: 0.270 AC: 41034 AN: 152146 Hom.: 10635 Cov.: 33 AF XY: 0.272 AC XY: 20254 AN XY: 74378

African (AFR) AF: 0.641 AC: 26595 AN: 41476

American (AMR) AF: 0.261 AC: 3993 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0860 AC: 298 AN: 3466

East Asian (EAS) AF: 0.584 AC: 3012 AN: 5160

South Asian (SAS) AF: 0.291 AC: 1405 AN: 4824

European-Finnish (FIN) AF: 0.0524 AC: 556 AN: 10612

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0660 AC: 4488 AN: 68000

Other (OTH) AF: 0.224 AC: 474 AN: 2114

Alfa AF: 0.183 Hom.: 755

Bravo AF: 0.305

Asia WGS AF: 0.458 AC: 1591 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.5
DANN	Benign	0.41
PhyloP100		-0.092
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: rs971696; hg19: chr4-110927865;