16-15720835-G-A
Variant summary
Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_002474.3(MYH11):c.4791+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,613,128 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_002474.3 splice_region, intron
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: Benign. The variant received -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH11 | NM_002474.3 | c.4791+4C>T | splice_region_variant, intron_variant | Intron 33 of 40 | ENST00000300036.6 | NP_002465.1 | ||
MYH11 | NM_001040113.2 | c.4812+4C>T | splice_region_variant, intron_variant | Intron 34 of 42 | ENST00000452625.7 | NP_001035202.1 | ||
NDE1 | NM_017668.3 | c.948-3356G>A | 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.4791+4C>T | splice_region_variant, intron_variant | Intron 33 of 40 | 1 | NM_002474.3 | ENSP00000300036.5 | |||
MYH11 | ENST00000452625.7 | c.4812+4C>T | splice_region_variant, intron_variant | Intron 34 of 42 | 1 | NM_001040113.2 | ENSP00000407821.2 | |||
NDE1 | ENST00000396354.6 | c.948-3356G>A | intron_variant | Intron 8 of 8 | 1 | NM_017668.3 | ENSP00000379642.1 |
Frequencies
GnomAD3 genomes AF: 0.00614 AC: 933AN: 152044Hom.: 8 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.00193 AC: 485AN: 250922 AF XY: 0.00144 show subpopulations
GnomAD4 exome AF: 0.00100 AC: 1461AN: 1460966Hom.: 7 Cov.: 32 AF XY: 0.000875 AC XY: 636AN XY: 726810 show subpopulations
GnomAD4 genome AF: 0.00611 AC: 930AN: 152162Hom.: 8 Cov.: 31 AF XY: 0.00570 AC XY: 424AN XY: 74384 show subpopulations
ClinVar
Submissions by phenotype
not specified Benign:3
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Variant summary: MYH11 c.4812+4C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0022 in 121360 control chromosomes in the ExAC database, including 2 homozygotes. The observed variant frequency is approximately 1740 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.4812+4C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
BS1,PB6,PB7. -
Familial thoracic aortic aneurysm and aortic dissection Benign:3
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This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
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Aortic aneurysm, familial thoracic 4 Benign: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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
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not provided Benign:1
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Connective tissue disorder Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at