rs11568848

Variant names:

• chr4-109913234-G-A
• rs11568848
• NM_001963.6:c.-102G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-109913234-G-A
• chr4-109913234-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001963.6(EGF):​c.-102G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,496,942 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: EGF NM_001963.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.879
• 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: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-109913234-G-A is Benign according to our data. Variant chr4-109913234-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 347223.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 169 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.-102G>A		5_prime_UTR_variant	Exon 1 of 24	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.-102G>A		5_prime_UTR_variant	Exon 1 of 23		NP_001171601.1
EGF	NM_001178131.3	c.-102G>A		5_prime_UTR_variant	Exon 1 of 23		NP_001171602.1
EGF	NM_001357021.2	c.-102G>A		5_prime_UTR_variant	Exon 1 of 20		NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10	c.-102G>A		5_prime_UTR_variant	Exon 1 of 24	1	NM_001963.6	ENSP00000265171.5
EGF	ENST00000509793.5	c.-102G>A		5_prime_UTR_variant	Exon 1 of 23	2		ENSP00000424316.1
EGF	ENST00000652245.1	c.-102G>A		5_prime_UTR_variant	Exon 1 of 20			ENSP00000498337.1
EGF	ENST00000503392.1	c.-102G>A		upstream_gene_variant		1		ENSP00000421384.1

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00145 AC: 1949 AN: 1344644 Hom.: 4 Cov.: 19 AF XY: 0.00149 AC XY: 1006 AN XY: 675162

African (AFR) AF: 0.000161 AC: 5 AN: 30992

American (AMR) AF: 0.000409 AC: 18 AN: 43996

Ashkenazi Jewish (ASJ) AF: 0.000480 AC: 12 AN: 24976

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38102

South Asian (SAS) AF: 0.00151 AC: 126 AN: 83294

European-Finnish (FIN) AF: 0.000105 AC: 5 AN: 47506

Middle Eastern (MID) AF: 0.00272 AC: 15 AN: 5518

European-Non Finnish (NFE) AF: 0.00168 AC: 1706 AN: 1014246

Other (OTH) AF: 0.00109 AC: 61 AN: 56014

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000913 AC XY: 68 AN XY: 74468

African (AFR) AF: 0.000409 AC: 17 AN: 41562

American (AMR) AF: 0.000719 AC: 11 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00176 AC: 120 AN: 68010

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000443 Hom.: 0

Bravo AF: 0.00108

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal hypomagnesemia 4 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	9.3
DANN	Benign	0.61
PhyloP100		-0.88
PromoterAI		-0.037	Neutral
Mutation Taster		=300/0	polymorphism

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: rs11568848; hg19: chr4-110834390; COSMIC: COSV54486216; COSMIC: COSV54486216;