19-42326320-G-T
Variant summary
Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting
The NM_001271938.2(MEGF8):c.77G>T(p.Arg26Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000708 in 1,566,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001271938.2 missense
Scores
Clinical Significance
Conservation
Publications
- MEGF8-related Carpenter syndromeInheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
- Carpenter syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MEGF8 | ENST00000251268.11 | c.77G>T | p.Arg26Leu | missense_variant | Exon 1 of 42 | 5 | NM_001271938.2 | ENSP00000251268.5 | ||
MEGF8 | ENST00000334370.8 | c.77G>T | p.Arg26Leu | missense_variant | Exon 1 of 41 | 1 | ENSP00000334219.4 | |||
MEGF8 | ENST00000378073.5 | c.-7009G>T | 5_prime_UTR_premature_start_codon_gain_variant | Exon 1 of 41 | 5 | ENSP00000367313.4 | ||||
MEGF8 | ENST00000378073.5 | c.-7009G>T | 5_prime_UTR_variant | Exon 1 of 41 | 5 | ENSP00000367313.4 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152212Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000808 AC: 16AN: 198142 AF XY: 0.0000723 show subpopulations
GnomAD4 exome AF: 0.0000735 AC: 104AN: 1414522Hom.: 0 Cov.: 30 AF XY: 0.0000796 AC XY: 56AN XY: 703882 show subpopulations
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152330Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74494 show subpopulations
ClinVar
Submissions by phenotype
not provided Uncertain:2
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
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Inborn genetic diseases Uncertain:1
The c.77G>T (p.R26L) alteration is located in exon 1 (coding exon 1) of the MEGF8 gene. This alteration results from a G to T substitution at nucleotide position 77, causing the arginine (R) at amino acid position 26 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
MEGF8-related Carpenter syndrome Uncertain:1
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 26 of the MEGF8 protein (p.Arg26Leu). This variant is present in population databases (rs377001753, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MEGF8-related conditions. ClinVar contains an entry for this variant (Variation ID: 1394338). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
MEGF8-related disorder Uncertain:1
The MEGF8 c.77G>T variant is predicted to result in the amino acid substitution p.Arg26Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.013% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-42830472-G-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at