rs777814775

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-3497349-C-A
• chr1-3497349-C-G
• chr1-3497349-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001409.4(MEGF6):​c.3365G>T​(p.Gly1122Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000717 in 1,393,822 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF6	NM_001409.4	c.3365G>T	p.Gly1122Val	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>T	p.Gly1122Val	missense_variant	Exon 27 of 37	1	NM_001409.4	ENSP00000348982.4
MEGF6	ENST00000294599.8	c.2792G>T	p.Gly931Val	missense_variant	Exon 22 of 30	1		ENSP00000294599.4
MEGF6	ENST00000697102.1	c.3050G>T	p.Gly1017Val	missense_variant	Exon 24 of 34			ENSP00000513108.1
MEGF6	ENST00000485002.6	n.3517G>T		non_coding_transcript_exon_variant	Exon 28 of 37	5		ENSP00000419033.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1393822 Hom.: 0 Cov.: 34 AF XY: 0.00000145 AC XY: 1 AN XY: 688798

African (AFR) AF: 0.00 AC: 0 AN: 30218

American (AMR) AF: 0.00 AC: 0 AN: 29292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22736

East Asian (EAS) AF: 0.00 AC: 0 AN: 38418

South Asian (SAS) AF: 0.00 AC: 0 AN: 76898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5260

European-Non Finnish (NFE) AF: 9.23e-7 AC: 1 AN: 1083608

Other (OTH) AF: 0.00 AC: 0 AN: 57180

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	.;T
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.51	T;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	4.3	.;H
PhyloP100		7.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-8.2	D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.70
MutPred		0.45		.;Loss of disorder (P = 0.0293);
MVP		0.95
MPC		0.58
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.88
gMVP		0.80
Mutation Taster		=37/63	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;