6-32166618-C-G

Variant names:

• chr6-32166618-C-G
• rs141826798
• NM_030652.4:c.222C>G

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

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]

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]

ACMG classification

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 rank	MANE	Protein	UniProt
EGFL8	NM_030652.4	c.222C>G	p.Tyr74*	stop_gained, splice_region_variant	Exon 3 of 9	ENST00000333845.11	NP_085155.1
EGFL8	NR_037860.2	n.337C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 9
PPT2-EGFL8	NR_037861.1	n.1739C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 10 of 16

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00326 AC: 497 AN: 152222 Hom.: 4 Cov.: 32

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.: 2 AF XY: 0.00309 AC XY: 420 AN XY: 135860

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.: 25 Cov.: 31 AF XY: 0.00437 AC XY: 3180 AN XY: 727244

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.: 4 Cov.: 32 AF XY: 0.00283 AC XY: 211 AN XY: 74492

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.: 5

Bravo AF: 0.00314

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000993 AC: 3

ESP6500EA AF: 0.00480 AC: 26

ExAC AF: 0.00314 AC: 381

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00534

EpiControl AF: 0.00640

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EGFL8: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.94	D
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

Other links and lift over

dbSNP: rs141826798; hg19: chr6-32134395; COSMIC: COSV99053430; COSMIC: COSV99053430;