rs886041239

Positions:

• chr10-110593202-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2 PP2 PP5_Very_Strong BP4

The NM_005445.4(SMC3):​c.1942A>G​(p.Met648Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMC3 NM_005445.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.10

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 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). GenCC has associacion of gene with Cornelia de Lange syndrome, Cornelia de Lange syndrome 3.
• PP5: Variant 10-110593202-A-G is Pathogenic according to our data. Variant chr10-110593202-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 279893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3904004). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMC3	NM_005445.4	c.1942A>G	p.Met648Val	missense_variant	18/29	ENST00000361804.5	NP_005436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMC3	ENST00000361804.5	c.1942A>G	p.Met648Val	missense_variant	18/29	1	NM_005445.4	ENSP00000354720	P1
SMC3	ENST00000684988.1	n.2587A>G		non_coding_transcript_exon_variant	16/25
SMC3	ENST00000692792.1	n.2061A>G		non_coding_transcript_exon_variant	18/19

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cornelia de Lange syndrome 3 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2022	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 648 of the SMC3 protein (p.Met648Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SMC3-related conditions (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 279893). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SMC3 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000279893, PMID:26633542). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26633542). A missense variant is a common mechanism . It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 04, 2016

The M648V pathogenic variant in the SMC3 gene has been reported previously as a somatic variant in a head and neck squamous cell carcinoma, but has not been reported in the germline (Stransky et al., 2011). The M648V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M648V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The M648V variant is located within the flexible hinge region of the protein, which is essential for protein function (Gruber et al., 2006). We interpret M648V as a pathogenic variant. -

Intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Medical Genetics Lab, Policlinico S. Orsola.Malpighi

Nov 09, 2018

The Met648Val variant in SMC3 is extremely rare (never reported in GnomAD exomes and genomes) and missense variants of this gene are a known cause of disease. Furthermore, this variant is de novo in the patient and there is no family history of the disease. On the other hand, prediction scores are conflicting (MutationTaster: disease-causing; SIFT: tolerated) and the clinical picture of this patient is not reminiscent of Cornelia de Lange syndrome. We interpret Met648Val as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	-0.22	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.59	N
REVEL	Uncertain	0.48
Sift	Benign	0.055	T
Sift4G	Benign	0.34	T
Polyphen		0.28	B
Vest4		0.56
MutPred		0.54		Loss of catalytic residue at M648 (P = 0.0123);
MVP		0.92
MPC		1.2
ClinPred		0.90	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.49
gMVP		0.94

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

Other links and lift over

dbSNP: rs886041239; hg19: chr10-112352960; COSMIC: COSV62421522;