rs769321167
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS1
The NM_002474.3(MYH11):c.1575+8delG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000535 in 1,614,186 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 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
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH11 | NM_002474.3 | c.1575+8delG | splice_region_variant, intron_variant | Intron 13 of 40 | ENST00000300036.6 | NP_002465.1 | ||
MYH11 | NM_001040113.2 | c.1596+8delG | splice_region_variant, intron_variant | Intron 14 of 42 | ENST00000452625.7 | NP_001035202.1 | ||
MYH11 | NM_001040114.2 | c.1596+8delG | splice_region_variant, intron_variant | Intron 14 of 41 | NP_001035203.1 | |||
MYH11 | NM_022844.3 | c.1575+8delG | splice_region_variant, intron_variant | Intron 13 of 41 | NP_074035.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH11 | ENST00000300036.6 | c.1575+8delG | splice_region_variant, intron_variant | Intron 13 of 40 | 1 | NM_002474.3 | ENSP00000300036.5 | |||
MYH11 | ENST00000452625.7 | c.1596+8delG | splice_region_variant, intron_variant | Intron 14 of 42 | 1 | NM_001040113.2 | ENSP00000407821.2 |
Frequencies
GnomAD3 genomes AF: 0.000296 AC: 45AN: 152178Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000207 AC: 52AN: 250854Hom.: 0 AF XY: 0.000243 AC XY: 33AN XY: 135676
GnomAD4 exome AF: 0.000560 AC: 818AN: 1461890Hom.: 1 Cov.: 32 AF XY: 0.000554 AC XY: 403AN XY: 727246
GnomAD4 genome AF: 0.000295 AC: 45AN: 152296Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13AN XY: 74474
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Benign:2
The variant is found in TAAD panel(s). -
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not provided Benign:2
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not specified Benign:1
Variant summary: MYH11 c.1596+8delG 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. 4/4 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 0.00021 in 250854 control chromosomes. The observed variant frequency is approximately 17 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Thoracic Aortic Aneurysms And Dissections phenotype (1.3e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1596+8delG in individuals affected with Thoracic Aortic Aneurysms And Dissections and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Aortic aneurysm, familial thoracic 4 Benign:1
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MYH11-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Aortic aneurysm, familial thoracic 4;C5543466:Visceral myopathy 2;C5543476:Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at