rs886058989

Variant names:

• chr4-109913071-G-T
• rs886058989
• NM_001963.6:c.-265G>T

Your query was ambiguous. Multiple possible variants found:

• chr4-109913071-G-T
• chr4-109913071-G-A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001963.6(EGF):​c.-265G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 265,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: EGF NM_001963.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53
• Publications: 0 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: Unknown, AR, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BS2: High AC in GnomAdExome4 at 8 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001963.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGF	NM_001963.6	MANE Select	c.-265G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 24	NP_001954.2	P01133-1
	EGF	NM_001963.6	MANE Select	c.-265G>T		5_prime_UTR	Exon 1 of 24	NP_001954.2	P01133-1
	EGF	NM_001178130.3		c.-265G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 23	NP_001171601.1	P01133-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGF	ENST00000265171.10	TSL:1 MANE Select	c.-265G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 24	ENSP00000265171.5	P01133-1
	EGF	ENST00000265171.10	TSL:1 MANE Select	c.-265G>T		5_prime_UTR	Exon 1 of 24	ENSP00000265171.5	P01133-1
	EGF	ENST00000868530.1		c.-265G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 24	ENSP00000538589.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000301 AC: 8 AN: 265552 Hom.: 0 Cov.: 3 AF XY: 0.0000415 AC XY: 6 AN XY: 144554

African (AFR) AF: 0.000132 AC: 1 AN: 7600

American (AMR) AF: 0.00 AC: 0 AN: 12932

Ashkenazi Jewish (ASJ) AF: 0.000831 AC: 6 AN: 7218

East Asian (EAS) AF: 0.00 AC: 0 AN: 13248

South Asian (SAS) AF: 0.00 AC: 0 AN: 42556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1018

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 155028

Other (OTH) AF: 0.0000712 AC: 1 AN: 14040

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Renal hypomagnesemia 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.83
PhyloP100		1.5
PromoterAI		-0.020	Neutral

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: rs886058989; hg19: chr4-110834227;