rs104893933
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM5PP3PP5_Very_Strong
The NM_000344.4(SMN1):c.346A>T(p.Ile116Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I116T) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 0)
Consequence
SMN1
NM_000344.4 missense
NM_000344.4 missense
Scores
3
6
8
Clinical Significance
Conservation
PhyloP100: -0.749
Genes affected
SMN1 (HGNC:11117): (survival of motor neuron 1, telomeric) This gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four genes and repetitive elements which make it prone to rearrangements and deletions. The repetitiveness and complexity of the sequence have also caused difficulty in determining the organization of this genomic region. The telomeric and centromeric copies of this gene are nearly identical and encode the same protein. However, mutations in this gene, the telomeric copy, are associated with spinal muscular atrophy; mutations in the centromeric copy do not lead to disease. The centromeric copy may be a modifier of disease caused by mutation in the telomeric copy. The critical sequence difference between the two genes is a single nucleotide in exon 7, which is thought to be an exon splice enhancer. Note that the nine exons of both the telomeric and centromeric copies are designated historically as exon 1, 2a, 2b, and 3-8. It is thought that gene conversion events may involve the two genes, leading to varying copy numbers of each gene. The protein encoded by this gene localizes to both the cytoplasm and the nucleus. Within the nucleus, the protein localizes to subnuclear bodies called gems which are found near coiled bodies containing high concentrations of small ribonucleoproteins (snRNPs). This protein forms heteromeric complexes with proteins such as SIP1 and GEMIN4, and also interacts with several proteins known to be involved in the biogenesis of snRNPs, such as hnRNP U protein and the small nucleolar RNA binding protein. Multiple transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2014]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM1
?
In a strand (size 9) in uniprot entity SMN_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000344.4
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr5-70942431-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3239631.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.823
PP5
?
Variant 5-70942430-A-T is Pathogenic according to our data. Variant chr5-70942430-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 9179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-70942430-A-T is described in UniProt as null. Variant chr5-70942430-A-T is described in UniProt as null. Variant chr5-70942430-A-T is described in UniProt as null. Variant chr5-70942430-A-T is described in UniProt as null. Variant chr5-70942430-A-T is described in UniProt as null. Variant chr5-70942430-A-T is described in UniProt as null. Variant chr5-70942430-A-T is described in UniProt as null. Variant chr5-70942430-A-T is described in UniProt as null. Variant chr5-70942430-A-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMN1 | NM_000344.4 | c.346A>T | p.Ile116Phe | missense_variant | 4/9 | ENST00000380707.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMN1 | ENST00000380707.9 | c.346A>T | p.Ile116Phe | missense_variant | 4/9 | 1 | NM_000344.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 0
GnomAD3 genomes
?
Cov.:
0
GnomAD4 exome Cov.: 0
GnomAD4 exome
Cov.:
0
GnomAD4 genome ? Cov.: 0
GnomAD4 genome
?
Cov.:
0
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 14, 2021 | Frequency data for this variant in the general population cannot be distinguished from that of the SMN2 gene, and is therefore uninformative in assessment of variant pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies indicate this variant leads to defective Sm core assembly (PMID: 16301532, 29982416). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. The variant is located in a region that is considered important for protein function and/or structure. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 27, 2023 | - - |
Werdnig-Hoffmann disease Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 15, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;.;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;.;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;.;D
Sift4G
Benign
T;T;T;T;T
Vest4
MutPred
Gain of catalytic residue at I116 (P = 0.0087);Gain of catalytic residue at I116 (P = 0.0087);Gain of catalytic residue at I116 (P = 0.0087);Gain of catalytic residue at I116 (P = 0.0087);Gain of catalytic residue at I116 (P = 0.0087);
MVP
MPC
2.1
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 12
Find out detailed SpliceAI scores and Pangolin per-transcript scores at