10-110602900-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_005445.4(SMC3):​c.3373C>A​(p.Leu1125Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

SMC3
NM_005445.4 missense

Scores

7
8
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.53
Variant links:
Genes affected
SMC3 (HGNC:2468): (structural maintenance of chromosomes 3) This gene belongs to the SMC3 subfamily of SMC proteins. The encoded protein occurs in certain cell types as either an intracellular, nuclear protein or a secreted protein. The nuclear form, known as structural maintenance of chromosomes 3, is a component of the multimeric cohesin complex that holds together sister chromatids during mitosis, enabling proper chromosome segregation. Post-translational modification of the encoded protein by the addition of chondroitin sulfate chains gives rise to the secreted proteoglycan bamacan, an abundant basement membrane protein. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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), SMC3. . Gene score misZ: 6.3999 (greater than the threshold 3.09). Trascript score misZ: 7.6232 (greater than threshold 3.09). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. GenCC has associacion of the gene with Cornelia de Lange syndrome, Cornelia de Lange syndrome 3.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.76

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMC3NM_005445.4 linkc.3373C>A p.Leu1125Ile missense_variant 27/29 ENST00000361804.5 NP_005436.1 Q9UQE7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMC3ENST00000361804.5 linkc.3373C>A p.Leu1125Ile missense_variant 27/291 NM_005445.4 ENSP00000354720.5 Q9UQE7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.040
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.23
T
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.76
D
MetaSVM
Uncertain
0.36
D
MutationAssessor
Benign
1.7
L
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-1.9
N
REVEL
Uncertain
0.60
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.69
MutPred
0.68
Gain of methylation at K1120 (P = 0.0457);
MVP
0.83
MPC
2.2
ClinPred
0.96
D
GERP RS
5.6
Varity_R
0.70
gMVP
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs901512521; hg19: chr10-112362658; API