NM_001963.6:c.2351A>T

Variant names:

• chr4-109980955-A-T
• rs11569017
• NM_001963.6:c.2351A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001963.6(EGF):​c.2351A>T​(p.Asp784Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.06 in 1,613,974 control chromosomes in the GnomAD database, including 3,671 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (367 hom., cov: 32)
  • Exomes 𝑓: 0.061 (3304 hom.)
• Consequence: EGF NM_001963.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.62
• Publications: 35 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 (MetaRNN=0.0013268888).
• BP6: Variant 4-109980955-A-T is Benign according to our data. Variant chr4-109980955-A-T is described in ClinVar as Benign. ClinVar VariationId is 347246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGF	NM_001963.6	c.2351A>T	p.Asp784Val	missense_variant	Exon 15 of 24	ENST00000265171.10	NP_001954.2
EGF	NM_001178130.3	c.2351A>T	p.Asp784Val	missense_variant	Exon 15 of 23		NP_001171601.1
EGF	NM_001178131.3	c.2225A>T	p.Asp742Val	missense_variant	Exon 14 of 23		NP_001171602.1
EGF	NM_001357021.2	c.2225A>T	p.Asp742Val	missense_variant	Exon 14 of 20		NP_001343950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGF	ENST00000265171.10	c.2351A>T	p.Asp784Val	missense_variant	Exon 15 of 24	1	NM_001963.6	ENSP00000265171.5

Frequencies

GnomAD3 genomes AF: 0.0530 AC: 8057 AN: 152082 Hom.: 367 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.0798

Gnomad ASJ AF: 0.0850

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.0711

Gnomad FIN AF: 0.0465

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0574

Gnomad OTH AF: 0.0612

GnomAD2 exomes AF: 0.0733 AC: 18423 AN: 251416 AF XY: 0.0729

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.0795

Gnomad EAS exome AF: 0.187

Gnomad FIN exome AF: 0.0537

Gnomad NFE exome AF: 0.0572

Gnomad OTH exome AF: 0.0701

GnomAD4 exome AF: 0.0607 AC: 88719 AN: 1461774 Hom.: 3304 Cov.: 31 AF XY: 0.0612 AC XY: 44476 AN XY: 727194

African (AFR) AF: 0.00911 AC: 305 AN: 33466

American (AMR) AF: 0.0985 AC: 4404 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0793 AC: 2072 AN: 26130

East Asian (EAS) AF: 0.202 AC: 8002 AN: 39692

South Asian (SAS) AF: 0.0733 AC: 6324 AN: 86256

European-Finnish (FIN) AF: 0.0565 AC: 3017 AN: 53416

Middle Eastern (MID) AF: 0.0562 AC: 324 AN: 5766

European-Non Finnish (NFE) AF: 0.0545 AC: 60553 AN: 1111938

Other (OTH) AF: 0.0616 AC: 3718 AN: 60392

GnomAD4 genome AF: 0.0530 AC: 8059 AN: 152200 Hom.: 367 Cov.: 32 AF XY: 0.0552 AC XY: 4108 AN XY: 74414

African (AFR) AF: 0.0116 AC: 482 AN: 41552

American (AMR) AF: 0.0797 AC: 1218 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0850 AC: 295 AN: 3472

East Asian (EAS) AF: 0.198 AC: 1022 AN: 5170

South Asian (SAS) AF: 0.0716 AC: 345 AN: 4818

European-Finnish (FIN) AF: 0.0465 AC: 492 AN: 10592

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0574 AC: 3906 AN: 67994

Other (OTH) AF: 0.0639 AC: 135 AN: 2112

Alfa AF: 0.0624 Hom.: 292

Bravo AF: 0.0529

TwinsUK AF: 0.0553 AC: 205

ALSPAC AF: 0.0524 AC: 202

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.0597 AC: 513

ExAC AF: 0.0704 AC: 8552

Asia WGS AF: 0.110 AC: 384 AN: 3478

EpiCase AF: 0.0593

EpiControl AF: 0.0581

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16574953) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Renal hypomagnesemia 4 Benign:1

Mar 06, 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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Uncertain	0.44	.;T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.83	T;T;T
MetaRNN	Benign	0.0013	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	.;L;L
PhyloP100		1.6
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-2.4	N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.0040	B;B;.
Vest4		0.18
MPC		0.26
ClinPred		0.013	T
GERP RS		3.7
Varity_R		0.50
gMVP		0.59
Mutation Taster		=86/14	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: rs11569017; hg19: chr4-110902111; COSMIC: COSV54483507; COSMIC: COSV54483507;