rs587784404

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP5_Moderate

The NM_006306.4(SMC1A):​c.1267C>A​(p.Gln423Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Q423Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Consequence

SMC1A
NM_006306.4 missense

Scores

4
6
7

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.73
Variant links:
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.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMC1A. . Gene score misZ 6.4479 (greater than the threshold 3.09). GenCC has associacion of gene with Cornelia de Lange syndrome, X-linked complex neurodevelopmental disorder, atypical Rett syndrome, Cornelia de Lange syndrome 2, developmental and epileptic encephalopathy, 85, with or without midline brain defects.
PP5
Variant X-53409491-G-T is Pathogenic according to our data. Variant chrX-53409491-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159940.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SMC1ANM_006306.4 linkuse as main transcriptc.1267C>A p.Gln423Lys missense_variant 8/25 ENST00000322213.9
SMC1ANM_001281463.1 linkuse as main transcriptc.1201C>A p.Gln401Lys missense_variant 9/26

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SMC1AENST00000322213.9 linkuse as main transcriptc.1267C>A p.Gln423Lys missense_variant 8/251 NM_006306.4 P1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Congenital muscular hypertrophy-cerebral syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.84
BayesDel_addAF
Uncertain
0.033
T
BayesDel_noAF
Benign
-0.19
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.46
T;T
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Pathogenic
0.78
D
MetaRNN
Uncertain
0.62
D;D
MetaSVM
Benign
-0.67
T
MutationAssessor
Benign
0.49
N;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.80
D
PROVEAN
Uncertain
-3.3
D;.
REVEL
Benign
0.25
Sift
Benign
0.20
T;.
Sift4G
Benign
0.24
T;T
Polyphen
0.47
P;.
Vest4
0.55
MutPred
0.49
Loss of ubiquitination at K424 (P = 0.0331);.;
MVP
0.89
MPC
2.7
ClinPred
0.96
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.86
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587784404; hg19: chrX-53436422; API