Variant 6-32166618-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_030652.4(EGFL8):c.222C>G(p.Tyr74*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00436 in 1,614,218 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0033 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 25 hom. )

Consequence

EGFL8
NM_030652.4 stop_gained, splice_region

Scores

Splicing: ADA: 0.5645

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.70

Variant links:

Genes affected

EGFL8 (HGNC:13944): (EGF like domain multiple 8) Predicted to enable signaling receptor binding activity. Predicted to be involved in anatomical structure development. Predicted to act upstream of or within in utero embryonic development. Predicted to be active in cell surface and extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

EGFL8 links:

PPT2-EGFL8 (HGNC:48343): (PPT2-EGFL8 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring PPT2 (palmitoyl-protein thioesterase 2) and EGFL8 (EGF-like-domain, multiple 8) genes located in the major histocompatibility complex class III region of chromosome 6. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

PPT2-EGFL8 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGFL8	NM_030652.4 link	c.222C>G	p.Tyr74*	stop_gained, splice_region_variant	3/9	ENST00000333845.11	NP_085155.1	Q99944A0A1U9X7N9
EGFL8	NR_037860.2 link	n.337C>G		splice_region_variant, non_coding_transcript_exon_variant	3/9
PPT2-EGFL8	NR_037861.1 link	n.1739C>G		splice_region_variant, non_coding_transcript_exon_variant	10/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
EGFL8	ENST00000333845.11 link	c.222C>G	p.Tyr74*	stop_gained, splice_region_variant	3/9	1	NM_030652.4	ENSP00000333380.6	Q99944
PPT2-EGFL8	ENST00000422437.5 link	n.*154C>G		splice_region_variant, non_coding_transcript_exon_variant	11/21	5		ENSP00000457534.1
PPT2-EGFL8	ENST00000422437.5 link	n.*154C>G		3_prime_UTR_variant	11/21	5		ENSP00000457534.1

Frequencies

GnomAD3 genomes

AF:

0.00326

AC:

497

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00588

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00299

AC:

752

AN:

251240

Hom.:

AF XY:

0.00309

AC XY:

420

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00513

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00448

AC:

6546

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00437

AC XY:

3180

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000806

Gnomad4 AMR exome

AF:

0.00179

Gnomad4 ASJ exome

AF:

0.00237

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000684

Gnomad4 FIN exome

AF:

0.00125

Gnomad4 NFE exome

AF:

0.00540

Gnomad4 OTH exome

AF:

0.00369

GnomAD4 genome

AF:

0.00326

AC:

497

AN:

152340

Hom.:

Cov.:

AF XY:

0.00283

AC XY:

211

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000986

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.000847

Gnomad4 NFE

AF:

0.00588

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00470

Hom.:

Bravo

AF:

0.00314

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000993

AC:

ESP6500EA

AF:

0.00480

AC:

ExAC

AF:

0.00314

AC:

381

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00534

EpiControl

AF:

0.00640

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2024

EGFL8: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.94

Vest4

0.46

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.56

dbscSNV1_RF

Pathogenic

0.73

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over