9-136668356-G-T

Variant names:

• chr9-136668356-G-T
• rs376703976
• NM_016215.5:c.74G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016215.5(EGFL7):​c.74G>T​(p.Arg25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,916 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R25Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EGFL7 NM_016215.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.235
• Publications: 0 publications found

Genes affected

EGFL7 (HGNC:20594): (EGF like domain multiple 7) This gene encodes a secreted endothelial cell protein that contains two epidermal growth factor-like domains. The encoded protein may play a role in regulating vasculogenesis. This protein may be involved in the growth and proliferation of tumor cells. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016215.5. 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
	EGFL7	NM_016215.5	MANE Select	c.74G>T	p.Arg25Leu	missense	Exon 4 of 11	NP_057299.1	Q9UHF1
	EGFL7	NM_201446.3		c.74G>T	p.Arg25Leu	missense	Exon 2 of 9	NP_958854.1	Q9UHF1
	EGFL7	NR_045110.2		n.400G>T		non_coding_transcript_exon	Exon 3 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFL7	ENST00000308874.12	TSL:1 MANE Select	c.74G>T	p.Arg25Leu	missense	Exon 4 of 11	ENSP00000307843.7	Q9UHF1
	EGFL7	ENST00000371698.3	TSL:1	c.74G>T	p.Arg25Leu	missense	Exon 2 of 9	ENSP00000360763.3	Q9UHF1
	EGFL7	ENST00000406555.7	TSL:1	c.74G>T	p.Arg25Leu	missense	Exon 3 of 10	ENSP00000385639.3	Q9UHF1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000437 AC: 1 AN: 228832 AF XY: 0.00000803

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000979

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445916 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 717862

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33216

American (AMR) AF: 0.00 AC: 0 AN: 43382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25328

East Asian (EAS) AF: 0.00 AC: 0 AN: 39446

South Asian (SAS) AF: 0.00 AC: 0 AN: 84132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5542

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1104130

Other (OTH) AF: 0.00 AC: 0 AN: 59582

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000832 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	-0.081	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.23
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.12	T
Polyphen		0.75	P
Vest4		0.60
MutPred		0.44		Loss of methylation at R25 (P = 0.0166)
MVP		0.93
MPC		0.33
ClinPred		0.82	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.17
gMVP		0.63
Mutation Taster		=77/23	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: rs376703976; hg19: chr9-139562808;