rs11569098

chr4-109999800-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001963.6(EGF):c.3127C>T(p.Leu1043Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,613,918 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0084 (22 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (15 hom.)
• Consequence: EGF NM_001963.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.54

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038739145).
• BP6: Variant 4-109999800-C-T is Benign according to our data. Variant chr4-109999800-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445644.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 = 0.00838 (1276/152258) while in subpopulation AFR AF= 0.0293 (1216/41544). AF 95% confidence interval is 0.0279. There are 22 homozygotes in gnomad4. There are 616 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGF	NM_001963.6	c.3127C>T	p.Leu1043Phe	missense_variant	21/24	ENST00000265171.10
EGF	NM_001178130.3	c.3004C>T	p.Leu1002Phe	missense_variant	20/23
EGF	NM_001178131.3	c.3001C>T	p.Leu1001Phe	missense_variant	20/23
EGF	NM_001357021.2	c.2758C>T	p.Leu920Phe	missense_variant	18/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGF	ENST00000265171.10	c.3127C>T	p.Leu1043Phe	missense_variant	21/24	1	NM_001963.6	P1

Frequencies

GnomAD3 genomes AF: 0.00837 AC: 1274 AN: 152140 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

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: 0.000103

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00224 AC: 562 AN: 251446 Hom.: 10 AF XY: 0.00140 AC XY: 190 AN XY: 135898

Gnomad AFR exome AF: 0.0313

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000850 AC: 1242 AN: 1461660 Hom.: 15 Cov.: 32 AF XY: 0.000700 AC XY: 509 AN XY: 727140

Gnomad4 AFR exome AF: 0.0301

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00838 AC: 1276 AN: 152258 Hom.: 22 Cov.: 32 AF XY: 0.00828 AC XY: 616 AN XY: 74434

Gnomad4 AFR AF: 0.0293

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00161 Hom.: 2

Bravo AF: 0.00959

ESP6500AA AF: 0.0313 AC: 138

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00278 AC: 338

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 27, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	18
Dann	Benign	0.97
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D;D;D
MetaRNN	Benign	0.0039	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Benign	0.073
Sift	Benign	0.044	D;D;D
Sift4G	Benign	0.064	T;T;T
Polyphen		0.063	B;B;.
Vest4		0.40
MVP		0.55
MPC		0.26
ClinPred		0.032	T
GERP RS		4.0
Varity_R		0.15
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11569098; hg19: chr4-110920956;