chr8-38169798-T-G
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_014462.3(LSM1):c.231+4A>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000402 in 1,518,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_014462.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LSM1 | NM_014462.3 | c.231+4A>C | splice_region_variant, intron_variant | Intron 3 of 3 | ENST00000311351.9 | NP_055277.1 | ||
LSM1 | NR_045492.2 | n.288+2167A>C | intron_variant | Intron 2 of 2 | ||||
LSM1 | NR_045493.1 | n.363+4A>C | splice_region_variant, intron_variant | Intron 3 of 3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000841 AC: 21AN: 249688Hom.: 0 AF XY: 0.0000741 AC XY: 10AN XY: 134934
GnomAD4 exome AF: 0.0000417 AC: 57AN: 1365852Hom.: 0 Cov.: 22 AF XY: 0.0000380 AC XY: 26AN XY: 684930
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74372
ClinVar
Submissions by phenotype
not provided Uncertain:1
- -
Constipation;C0010417:Cryptorchidism;C0019294:Inguinal hernia;C0026269:Mitral stenosis;C0038379:Strabismus;C0079924:Oligohydramnios;C0149630:Bicuspid aortic valve;C0232466:Feeding difficulties;C0241397:Triphalangeal thumb;C0265677:Hemivertebrae;C0344925:Perimembranous ventricular septal defect;C0424503:Abnormal facial shape;C0521620:Hydroureter;C1691215:Penile hypospadias;C1858120:Generalized hypotonia;C2317073:Fetal pyelectasis;C3714756:Intellectual disability;C4022738:Neurodevelopmental delay;C4023248:Patent ductus arteriosus after premature birth Uncertain:1
This variant is classified as VUS since this is the first report associating a human congenital disorder with the gene but the evidence favors pathogenicity and causality. -
Complex neurodevelopmental disorder Uncertain:1
The homozygous c.231+4A>C variant in LSM1 was identified by our study in collaboration with the Chung Lab in 2 siblings with multiple congenital anomalies and global developmental delay (PMID: 31010896). This variant has also been reported as a VUS by the Wendy Chung Laboratory in ClinVar (Variation ID: 623485). This variant has been identified in 0.190% (19/10022) of Ashkenazi Jewish chromosomes and 0.002% (2/113204) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs775468919). Although this variant has been seen in the general population, its frequency is not high enough to rule out an impact to the protein. In vitro functional studies with patient peripheral blood provide some evidence that the c.231+4A>C variant may slightly impact protein splicing (PMID: 31010896). However, these types of assays may not accurately represent biological function. This variant is located in the 5' splice region. Computational tools do suggest a weak impact to splicing. However, this information is not predictive enough to determine impact to the protein. The presence of this variant in affected homozygotes increases the likelihood that the c.231+4A>C variant is pathogenic (PMID: 31010896). Furthermore, although this gene has been reported in association with multiple congenital anomalies and global developmental delay, it currently has limited evidence for these associations. In summary, the clinical significance of the c.231+4A>C variant is uncertain. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at