6-32167912-T-A

Variant names:

• chr6-32167912-T-A
• rs767399890
• NM_030652.4:c.838T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_030652.4(EGFL8):​c.838T>A​(p.Ser280Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. S280A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EGFL8 NM_030652.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.552
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2654773).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030652.4. 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
	EGFL8	NM_030652.4	MANE Select	c.838T>A	p.Ser280Thr	missense splice_region	Exon 9 of 9	NP_085155.1	Q99944
	EGFL8	NR_037860.2		n.953T>A		splice_region non_coding_transcript_exon	Exon 9 of 9
	PPT2-EGFL8	NR_037861.1		n.2355T>A		splice_region non_coding_transcript_exon	Exon 16 of 16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFL8	ENST00000333845.11	TSL:1 MANE Select	c.838T>A	p.Ser280Thr	missense splice_region	Exon 9 of 9	ENSP00000333380.6	Q99944
	EGFL8	ENST00000395512.5	TSL:1	c.838T>A	p.Ser280Thr	missense splice_region	Exon 9 of 9	ENSP00000378888.1	Q99944
	PPT2-EGFL8	ENST00000422437.5	TSL:5	n.*754T>A		splice_region non_coding_transcript_exon	Exon 17 of 21	ENSP00000457534.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0097	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.55
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.010	D
Polyphen		0.14	B
Vest4		0.25
MutPred		0.34		Loss of disorder (P = 0.0351)
MVP		0.96
MPC		0.44
ClinPred		0.65	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.049
gMVP		0.49
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs767399890; hg19: chr6-32135689;