rs35397046

Variant names:

• chr4-109912912-G-A
• rs35397046
• NM_001963.6:c.-424G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-109912912-G-A
• chr4-109912912-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001963.6(EGF):​c.-424G>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 0.00639 in 188,554 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (14 hom., cov: 33)
  • Exomes 𝑓: 0.00069 (0 hom.)
• Consequence: EGF NM_001963.6 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.98
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 4-109912912-G-A is Benign according to our data. Variant chr4-109912912-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 901088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00774 (1179/152288) while in subpopulation AFR AF = 0.0268 (1114/41548). AF 95% confidence interval is 0.0255. There are 14 homozygotes in GnomAd4. There are 531 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1179 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.-424G>A		5_prime_UTR_variant	Exon 1 of 24	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.-424G>A		5_prime_UTR_variant	Exon 1 of 23		NP_001171601.1
EGF	NM_001178131.3	c.-424G>A		5_prime_UTR_variant	Exon 1 of 23		NP_001171602.1
EGF	NM_001357021.2	c.-424G>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.-424G>A		5_prime_UTR_variant	Exon 1 of 24	1	NM_001963.6	ENSP00000265171.5
EGF	ENST00000509793.5	c.-424G>A		5_prime_UTR_variant	Exon 1 of 23	2		ENSP00000424316.1
EGF	ENST00000652245.1	c.-424G>A		5_prime_UTR_variant	Exon 1 of 20			ENSP00000498337.1

Frequencies

GnomAD3 genomes AF: 0.00774 AC: 1178 AN: 152170 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00383

GnomAD4 exome AF: 0.000689 AC: 25 AN: 36266 Hom.: 0 Cov.: 0 AF XY: 0.000760 AC XY: 14 AN XY: 18416

African (AFR) AF: 0.0168 AC: 12 AN: 714

American (AMR) AF: 0.00190 AC: 6 AN: 3156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 686

East Asian (EAS) AF: 0.00 AC: 0 AN: 2078

South Asian (SAS) AF: 0.000471 AC: 2 AN: 4244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 102

European-Non Finnish (NFE) AF: 0.0000458 AC: 1 AN: 21828

Other (OTH) AF: 0.00202 AC: 4 AN: 1978

GnomAD4 genome AF: 0.00774 AC: 1179 AN: 152288 Hom.: 14 Cov.: 33 AF XY: 0.00713 AC XY: 531 AN XY: 74460

African (AFR) AF: 0.0268 AC: 1114 AN: 41548

American (AMR) AF: 0.00281 AC: 43 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68024

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00360 Hom.: 1

Bravo AF: 0.00884

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Mar 16, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Renal hypomagnesemia 4 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.9
DANN	Benign	0.68
PhyloP100		-2.0
PromoterAI		-0.059	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: rs35397046; hg19: chr4-110834068;