6-32166788-C-G

Variant names:

• chr6-32166788-C-G
• NM_030652.4:c.312C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030652.4(EGFL8):​c.312C>G​(p.His104Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EGFL8 NM_030652.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0320

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGFL8	NM_030652.4	c.312C>G	p.His104Gln	missense_variant	Exon 4 of 9	ENST00000333845.11	NP_085155.1
EGFL8	NR_037860.2	n.427C>G		non_coding_transcript_exon_variant	Exon 4 of 9
PPT2-EGFL8	NR_037861.1	n.1829C>G		non_coding_transcript_exon_variant	Exon 11 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGFL8	ENST00000333845.11	c.312C>G	p.His104Gln	missense_variant	Exon 4 of 9	1	NM_030652.4	ENSP00000333380.6
PPT2-EGFL8	ENST00000422437.5	n.*244C>G		non_coding_transcript_exon_variant	Exon 12 of 21	5		ENSP00000457534.1
PPT2-EGFL8	ENST00000422437.5	n.*244C>G		3_prime_UTR_variant	Exon 12 of 21	5		ENSP00000457534.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.312C>G (p.H104Q) alteration is located in exon 4 (coding exon 3) of the EGFL8 gene. This alteration results from a C to G substitution at nucleotide position 312, causing the histidine (H) at amino acid position 104 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.048	T;T;.
Eigen	Benign	0.10
Eigen_PC	Benign	0.0059
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.69	.;T;T
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Uncertain	0.045	D
MutationAssessor	Uncertain	2.3	M;M;.
PROVEAN	Uncertain	-4.1	D;D;D
REVEL	Uncertain	0.48
Sift	Benign	0.066	T;T;T
Sift4G	Uncertain	0.029	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.38
MutPred		0.54		Gain of catalytic residue at H104 (P = 0.0379);Gain of catalytic residue at H104 (P = 0.0379);Gain of catalytic residue at H104 (P = 0.0379);
MVP		0.97
MPC		1.3
ClinPred		0.97	D
GERP RS		-1.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.089
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-32134565;