chr16-15717314-C-T
Variant summary
Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP3_ModerateBS1_Supporting
The NM_002474.3(MYH11):c.5330G>A(p.Arg1777His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,611,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1777C) has been classified as Uncertain significance.
Frequency
Consequence
NM_002474.3 missense
Scores
Clinical Significance
Conservation
Publications
- lissencephaly 4Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
- hydranencephalyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- microlissencephalyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- NDE1-related microhydranencephalyInheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH11 | NM_002474.3 | c.5330G>A | p.Arg1777His | missense_variant | Exon 38 of 41 | ENST00000300036.6 | NP_002465.1 | |
MYH11 | NM_001040113.2 | c.5351G>A | p.Arg1784His | missense_variant | Exon 39 of 43 | ENST00000452625.7 | NP_001035202.1 | |
NDE1 | NM_017668.3 | c.948-6877C>T | intron_variant | Intron 8 of 8 | ENST00000396354.6 | NP_060138.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH11 | ENST00000300036.6 | c.5330G>A | p.Arg1777His | missense_variant | Exon 38 of 41 | 1 | NM_002474.3 | ENSP00000300036.5 | ||
MYH11 | ENST00000452625.7 | c.5351G>A | p.Arg1784His | missense_variant | Exon 39 of 43 | 1 | NM_001040113.2 | ENSP00000407821.2 | ||
NDE1 | ENST00000396354.6 | c.948-6877C>T | intron_variant | Intron 8 of 8 | 1 | NM_017668.3 | ENSP00000379642.1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152226Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000805 AC: 2AN: 248536 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000754 AC: 11AN: 1458916Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 4AN XY: 725932 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000525 AC: 8AN: 152344Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74492 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Aortic aneurysm, familial thoracic 4 Uncertain:2
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1784 of the MYH11 protein (p.Arg1784His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MYH11-related conditions. ClinVar contains an entry for this variant (Variation ID: 318096). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH11 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. -
Lissencephaly, Recessive Uncertain:1
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Aortic aneurysm, familial thoracic 4;C5543466:Visceral myopathy 2;C5543476:Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at