10-110599723-G-C

Position:

• chr10-110599723-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_005445.4(SMC3):​c.2338G>C​(p.Glu780Gln) 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMC3 NM_005445.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.33

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 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), 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.
• PP5: Variant 10-110599723-G-C is Pathogenic according to our data. Variant chr10-110599723-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159976.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMC3	NM_005445.4	c.2338G>C	p.Glu780Gln	missense_variant	21/29	ENST00000361804.5	NP_005436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMC3	ENST00000361804.5	c.2338G>C	p.Glu780Gln	missense_variant	21/29	1	NM_005445.4	ENSP00000354720.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cornelia de Lange syndrome 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 01, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.085	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.51
Sift	Benign	0.10	T
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.57
MutPred		0.43		Loss of stability (P = 0.2641);
MVP		0.77
MPC		2.2
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.35
gMVP		0.45

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: rs587784427; hg19: chr10-112359481;