6-32166978-G-T

Variant names:

• chr6-32166978-G-T
• rs893227725
• NM_030652.4:c.403G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_030652.4(EGFL8):​c.403G>T​(p.Gly135Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EGFL8 NM_030652.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.71

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGFL8	NM_030652.4	c.403G>T	p.Gly135Cys	missense_variant	Exon 5 of 9	ENST00000333845.11	NP_085155.1
EGFL8	NR_037860.2	n.518G>T		non_coding_transcript_exon_variant	Exon 5 of 9
PPT2-EGFL8	NR_037861.1	n.1920G>T		non_coding_transcript_exon_variant	Exon 12 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGFL8	ENST00000333845.11	c.403G>T	p.Gly135Cys	missense_variant	Exon 5 of 9	1	NM_030652.4	ENSP00000333380.6
PPT2-EGFL8	ENST00000422437.5	n.*335G>T		non_coding_transcript_exon_variant	Exon 13 of 21	5		ENSP00000457534.1
PPT2-EGFL8	ENST00000422437.5	n.*335G>T		3_prime_UTR_variant	Exon 13 of 21	5		ENSP00000457534.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460780 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726712

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;H;.
PROVEAN	Pathogenic	-8.2	D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.71
MutPred		0.81		Loss of ubiquitination at K139 (P = 0.0755);Loss of ubiquitination at K139 (P = 0.0755);Loss of ubiquitination at K139 (P = 0.0755);
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.29
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs893227725; hg19: chr6-32134755;