rs1556885815
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP2PP3_Strong
The NM_006306.4(SMC1A):āc.3468T>Gā(p.Asp1156Glu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000037 ( 0 hom., 0 hem., cov: 22)
Exomes š: 0.0034 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
SMC1A
NM_006306.4 missense
NM_006306.4 missense
Scores
12
4
1
Clinical Significance
Conservation
PhyloP100: 4.38
Genes affected
SMC1A (HGNC:11111): (structural maintenance of chromosomes 1A) Proper cohesion of sister chromatids is a prerequisite for the correct segregation of chromosomes during cell division. The cohesin multiprotein complex is required for sister chromatid cohesion. This complex is composed partly of two structural maintenance of chromosomes (SMC) proteins, SMC3 and either SMC1B or the protein encoded by this gene. Most of the cohesin complexes dissociate from the chromosomes before mitosis, although those complexes at the kinetochore remain. Therefore, the encoded protein is thought to be an important part of functional kinetochores. In addition, this protein interacts with BRCA1 and is phosphorylated by ATM, indicating a potential role for this protein in DNA repair. This gene, which belongs to the SMC gene family, is located in an area of the X-chromosome that escapes X inactivation. Mutations in this gene result in Cornelia de Lange syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, SMC1A
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.974
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMC1A | NM_006306.4 | c.3468T>G | p.Asp1156Glu | missense_variant | 23/25 | ENST00000322213.9 | |
SMC1A | NM_001281463.1 | c.3402T>G | p.Asp1134Glu | missense_variant | 24/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMC1A | ENST00000322213.9 | c.3468T>G | p.Asp1156Glu | missense_variant | 23/25 | 1 | NM_006306.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 4AN: 108590Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 31344 FAILED QC
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00340 AC: 3575AN: 1052218Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 341022
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.0000368 AC: 4AN: 108649Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 31405
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
Developmental and epileptic encephalopathy, 85, with or without midline brain defects Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant c.3468T>Gp.Asp1156Glu in SMC1A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Asp1156Glu variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain_significance with a status of criteria provided, single submitter. The amino acid change p.Asp1156Glu in SMC1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asp at position 1156 is changed to a Glu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance VUS. - |
Congenital muscular hypertrophy-cerebral syndrome;C5393312:Developmental and epileptic encephalopathy, 85, with or without midline brain defects Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 12, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Loss of catalytic residue at D1159 (P = 0.2854);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at