chrX-13594880-A-T

Variant names:

• chrX-13594880-A-T
• rs775266200
• NM_015507.4:c.232A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015507.4(EGFL6):​c.232A>T​(p.Asn78Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,410 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 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. N78D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: EGFL6 NM_015507.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.08
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015507.4. 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
	EGFL6	NM_015507.4	MANE Select	c.232A>T	p.Asn78Tyr	missense	Exon 3 of 12	NP_056322.2
	EGFL6	NM_001167890.2		c.232A>T	p.Asn78Tyr	missense	Exon 3 of 12	NP_001161362.1	Q8IUX8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFL6	ENST00000361306.6	TSL:1 MANE Select	c.232A>T	p.Asn78Tyr	missense	Exon 3 of 12	ENSP00000355126.1	Q8IUX8-1
	EGFL6	ENST00000380602.3	TSL:1	c.232A>T	p.Asn78Tyr	missense	Exon 3 of 12	ENSP00000369976.3	Q8IUX8-2
	EGFL6	ENST00000857787.1		c.232A>T	p.Asn78Tyr	missense	Exon 3 of 11	ENSP00000527846.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097410 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362816

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26393

American (AMR) AF: 0.00 AC: 0 AN: 35189

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19360

East Asian (EAS) AF: 0.00 AC: 0 AN: 30193

South Asian (SAS) AF: 0.00 AC: 0 AN: 53981

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40499

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4124

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841618

Other (OTH) AF: 0.00 AC: 0 AN: 46053

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.86	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	-0.88	N
PhyloP100		7.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.086	T
Polyphen		0.91	P
Vest4		0.77
MutPred		0.50		Loss of disorder (P = 0.0738)
MVP		0.72
MPC		0.74
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.91
gMVP		0.75
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs775266200; hg19: chrX-13612999;