15-65922377-C-G

Variant summary

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

The NM_001385028.1(MEGF11):c.1918G>C(p.Glu640Gln) variant causes a missense change involving the alteration of a 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: 32)
• Consequence: MEGF11 NM_001385028.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

MEGF11 (HGNC:29635): (multiple EGF like domains 11) Predicted to be involved in homotypic cell-cell adhesion and retina layer formation. Predicted to be located in basolateral plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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/exons	MANE	UniProt
MEGF11	NM_001385028.1	c.1918G>C	p.Glu640Gln	missense_variant	15/26	ENST00000395614.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF11	ENST00000395614.6	c.1918G>C	p.Glu640Gln	missense_variant	15/26	5	NM_001385028.1	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Dec 15, 2023

The c.1918G>C (p.E640Q) alteration is located in exon 15 (coding exon 14) of the MEGF11 gene. This alteration results from a G to C substitution at nucleotide position 1918, causing the glutamic acid (E) at amino acid position 640 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	Benign	0.088
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.014	T;.;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.50	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.17	N;.;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.86	N;N;N;.
REVEL	Benign	0.14
Sift	Benign	0.26	T;T;T;.
Sift4G	Benign	0.47	T;T;T;T
Polyphen		0.96	D;D;D;.
Vest4		0.36
MutPred		0.33		Gain of disorder (P = 0.1147);.;Gain of disorder (P = 0.1147);Gain of disorder (P = 0.1147);
MVP		0.46
MPC		0.19
ClinPred		0.88	D
GERP RS		5.1
Varity_R		0.22
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-66214715;