rs1057516996
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_001164507.2(NEB):c.7228-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001164507.2 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.7228-1G>A | splice_acceptor_variant | ENST00000427231.7 | |||
NEB | NM_001164508.2 | c.7228-1G>A | splice_acceptor_variant | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.7228-1G>A | splice_acceptor_variant | 5 | NM_001164508.2 | P5 | |||
NEB | ENST00000427231.7 | c.7228-1G>A | splice_acceptor_variant | 5 | NM_001164507.2 | A2 | |||
NEB | ENST00000409198.5 | c.7228-1G>A | splice_acceptor_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152108Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461030Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726810
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152108Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74296
ClinVar
Submissions by phenotype
Nemaline myopathy 2 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 23, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 09, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 371087). This variant is also known as g.82777G>A. Disruption of this splice site has been observed in individuals with nemaline myopathy (PMID: 16917880; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 53 of the NEB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 21, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Nemaline myopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | research | Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire | Mar 01, 2024 | PVS1+PS3+PM1+PM2+PM3+PP3+PP4+PP5 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 26, 2021 | Variant summary: NEB c.7228-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 248554 control chromosomes (gnomAD). c.7228-1G>A has been reported in the literature (as g.82777G>A) in a compound heterozygous individual affected with typical form of Nemaline Myopathy (Lehtokari_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Arthrogryposis multiplex congenita 6 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 05, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at