X-13594844-G-A

Position:

• chrX-13594844-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000361306.6(EGFL6):​c.196G>A​(p.Glu66Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,207,051 control chromosomes in the GnomAD database, including 68 homozygotes. There are 942 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.016 (33 hom., 467 hem., cov: 23)
  • Exomes 𝑓: 0.0017 (35 hom. 475 hem.)
• Consequence: EGFL6 ENST00000361306.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.57

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003242433).
• BP6: Variant X-13594844-G-A is Benign according to our data. Variant chrX-13594844-G-A is described in ClinVar as [Benign]. Clinvar id is 712289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGFL6	NM_015507.4	c.196G>A	p.Glu66Lys	missense_variant	3/12	ENST00000361306.6	NP_056322.2
EGFL6	NM_001167890.2	c.196G>A	p.Glu66Lys	missense_variant	3/12		NP_001161362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGFL6	ENST00000361306.6	c.196G>A	p.Glu66Lys	missense_variant	3/12	1	NM_015507.4	ENSP00000355126	A2
EGFL6	ENST00000380602.3	c.196G>A	p.Glu66Lys	missense_variant	3/12	1		ENSP00000369976	P4

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 1733 AN: 111521 Hom.: 33 Cov.: 23 AF XY: 0.0137 AC XY: 462 AN XY: 33729

Gnomad AFR AF: 0.0539

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00514

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.000263

Gnomad OTH AF: 0.0128

GnomAD3 exomes AF: 0.00465 AC: 848 AN: 182351 Hom.: 12 AF XY: 0.00326 AC XY: 218 AN XY: 66873

Gnomad AFR exome AF: 0.0558

Gnomad AMR exome AF: 0.00332

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000726

Gnomad SAS exome AF: 0.000212

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00171 AC: 1878 AN: 1095476 Hom.: 35 Cov.: 29 AF XY: 0.00132 AC XY: 475 AN XY: 360998

Gnomad4 AFR exome AF: 0.0542

Gnomad4 AMR exome AF: 0.00373

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000663

Gnomad4 SAS exome AF: 0.0000932

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000173

Gnomad4 OTH exome AF: 0.00352

GnomAD4 genome AF: 0.0156 AC: 1741 AN: 111575 Hom.: 33 Cov.: 23 AF XY: 0.0138 AC XY: 467 AN XY: 33793

Gnomad4 AFR AF: 0.0540

Gnomad4 AMR AF: 0.00513

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000263

Gnomad4 OTH AF: 0.0127

Alfa AF: 0.00243 Hom.: 95

Bravo AF: 0.0177

ESP6500AA AF: 0.0532 AC: 204

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00524 AC: 636

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 15, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0063	T;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D;D
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.12	N;N
MutationTaster	Benign	0.75	P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.094
Sift	Uncertain	0.025	D;D
Sift4G	Benign	0.57	T;T
Polyphen		0.76	P;P
Vest4		0.16
MVP		0.58
MPC		0.34
ClinPred		0.016	T
GERP RS		3.2
Varity_R		0.18
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs16979010; hg19: chrX-13612963; COSMIC: COSV100768723; COSMIC: COSV100768723;