NM_005445.4:c.707G>C

Variant names:

• chr10-110582082-G-C
• rs587784429
• NM_005445.4:c.707G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_005445.4(SMC3):​c.707G>C​(p.Arg236Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R236H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMC3 NM_005445.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.53
• Publications: 7 publications found

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]

SMC3 Gene-Disease associations (from GenCC):

• Cornelia de Lange syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Cornelia de Lange syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a coiled_coil_region (size 171) in uniprot entity SMC3_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_005445.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-110582082-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2576559.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the SMC3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 6.3999 (above the threshold of 3.09). Trascript score misZ: 7.6232 (above the threshold of 3.09). GenCC associations: The gene is linked to Cornelia de Lange syndrome 3, Cornelia de Lange syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89
• PP5: Variant 10-110582082-G-C is Pathogenic according to our data. Variant chr10-110582082-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 159990.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005445.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC3	NM_005445.4	MANE Select	c.707G>C	p.Arg236Pro	missense	Exon 9 of 29	NP_005436.1	Q9UQE7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC3	ENST00000361804.5	TSL:1 MANE Select	c.707G>C	p.Arg236Pro	missense	Exon 9 of 29	ENSP00000354720.5	Q9UQE7
	SMC3	ENST00000918257.1		c.707G>C	p.Arg236Pro	missense	Exon 9 of 29	ENSP00000588316.1
	SMC3	ENST00000966376.1		c.725G>C	p.Arg242Pro	missense	Exon 9 of 29	ENSP00000636435.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Cornelia de Lange syndrome 3 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.5
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.68		Loss of MoRF binding (P = 0.068)
MVP		0.95
MPC		2.6
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.89
gMVP		0.99
Mutation Taster		=49/51	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587784429; hg19: chr10-112341840;