X-13603356-G-A

Position:

• chrX-13603356-G-A

Variant summary

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

The NM_015507.4(EGFL6):​c.440G>A​(p.Cys147Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,096,688 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: EGFL6 NM_015507.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

EGFL6 (HGNC:3235): (EGF like domain multiple 6) This gene encodes a member of the epidermal growth factor (EGF) repeat superfamily. Members of this superfamily are characterized by the presence of EGF-like repeats and are often involved in the regulation of cell cycle, proliferation, and developmental processes. The gene product contains a signal peptide, suggesting that it is secreted; an EGF repeat region consisting of 4 complete EGF-like repeats and 1 partial EGF-like repeat, 3 of which have a calcium-binding consensus sequence; an arg-gly-asp integrin association motif; and a MAM domain, which is believed to have an adhesive function. This gene is expressed early during development, and its expression has been detected in lung and meningioma tumors. [provided by RefSeq, Jul 2008]

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, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGFL6	NM_015507.4	c.440G>A	p.Cys147Tyr	missense_variant	5/12	ENST00000361306.6	NP_056322.2
EGFL6	NM_001167890.2	c.440G>A	p.Cys147Tyr	missense_variant	5/12		NP_001161362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGFL6	ENST00000361306.6	c.440G>A	p.Cys147Tyr	missense_variant	5/12	1	NM_015507.4	ENSP00000355126	A2
EGFL6	ENST00000380602.3	c.440G>A	p.Cys147Tyr	missense_variant	5/12	1		ENSP00000369976	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1096688 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 362088

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: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2024

The c.440G>A (p.C147Y) alteration is located in exon 5 (coding exon 5) of the EGFL6 gene. This alteration results from a G to A substitution at nucleotide position 440, causing the cysteine (C) at amino acid position 147 to be replaced by a tyrosine (Y). 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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.72
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.78	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-11	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.91		Gain of phosphorylation at C147 (P = 0.067);Gain of phosphorylation at C147 (P = 0.067);
MVP		0.68
MPC		1.1
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1166762061; hg19: chrX-13621475;