1-3497349-C-G

Variant names:

• chr1-3497349-C-G
• rs777814775
• NM_001409.4:c.3365G>C

Variant summary

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

The NM_001409.4(MEGF6):​c.3365G>C​(p.Gly1122Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. G1122D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: MEGF6 NM_001409.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.15
• Publications: 0 publications found

Genes affected

MEGF6 (HGNC:3232): (multiple EGF like domains 6) Predicted to enable calcium ion binding activity. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.768

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF6	NM_001409.4	c.3365G>C	p.Gly1122Ala	missense_variant	Exon 27 of 37	ENST00000356575.9	NP_001400.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF6	ENST00000356575.9	c.3365G>C	p.Gly1122Ala	missense_variant	Exon 27 of 37	1	NM_001409.4	ENSP00000348982.4
MEGF6	ENST00000294599.8	c.2792G>C	p.Gly931Ala	missense_variant	Exon 22 of 30	1		ENSP00000294599.4
MEGF6	ENST00000697102.1	c.3050G>C	p.Gly1017Ala	missense_variant	Exon 24 of 34			ENSP00000513108.1
MEGF6	ENST00000485002.6	n.3517G>C		non_coding_transcript_exon_variant	Exon 28 of 37	5		ENSP00000419033.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.52	T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	4.1	.;H
PhyloP100		7.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		1.0	D;D
Vest4		0.60
MutPred		0.33		.;Loss of disorder (P = 0.1533);
MVP		0.91
MPC		0.52
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.69
gMVP		0.70
Mutation Taster		=43/57	disease causing

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

Other links and lift over

dbSNP: rs777814775; hg19: chr1-3413913;