chr3-123664174-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP2PP3_Strong
The NM_053025.4(MYLK):c.3916G>A(p.Gly1306Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,614,034 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. G1306A) has been classified as Uncertain significance.
Frequency
Consequence
NM_053025.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYLK | NM_053025.4 | c.3916G>A | p.Gly1306Ser | missense_variant | 23/34 | ENST00000360304.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYLK | ENST00000360304.8 | c.3916G>A | p.Gly1306Ser | missense_variant | 23/34 | 5 | NM_053025.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251350Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135862
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461856Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727226
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74348
ClinVar
Submissions by phenotype
Aortic aneurysm, familial thoracic 7 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Sep 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal dominant familial thoracic aortic aneurysm 7 (MIM#613780). It has also been reported for autosomal recessive megacystis-microcolon-intestinal hypoperistalsis syndrome 1 (MIM#249210), however this gene-disease association has not been established conclusively (PanelApp Australia). (I) 0107 - This gene is associated with autosomal dominant familial thoracic aortic aneurysm 7 (MIM#613780) although homozygotes with more early-onset severe disease have also been reported (PMID: 29544503; OMIM). It has also been associated with autosomal recessive megacystis-microcolon-intestinal hypoperistalsis syndrome 1 (MIM#249210), however this gene-disease association has not been established conclusively (PanelApp Australia). (I) 0112 - The familial thoracic aortic aneurysm 7 associated with this gene has incomplete penetrance (PMIDs: 29544503, 21055718; OMIM). (I) 0115 - Variants associated with familial thoracic aortic aneurysm 7 in this gene are known to have variable expressivity (PMIDs: 29544503, 21055718). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2 & v3: 5 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2 & v3: 2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated immunoglobulin I-set domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as a VUS by a clinical testing laboratory in three unrelated individuals with connective tissue features (mainly in skeletal tissue or joint) and an unaffected parent, an individual with non aortic-related artery disease, and an individual with a family history of aortic aneurysm who was positive for a known familial variant in an alternative gene associated with aortic aneurysm (ClinVar, personal communication). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1306 of the MYLK protein (p.Gly1306Ser). This variant is present in population databases (rs755117377, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MYLK-related conditions. ClinVar contains an entry for this variant (Variation ID: 409712). 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 MYLK protein function with a negative predictive value of 80%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at