rs142524280

Variant names:

• chr10-110584371-A-G
• rs142524280
• NM_005445.4:c.1280A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_005445.4(SMC3):​c.1280A>G​(p.Lys427Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000379 in 1,613,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: SMC3 NM_005445.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 8.88
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.014473438).
• BP6: Variant 10-110584371-A-G is Benign according to our data. Variant chr10-110584371-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159966.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000525 (80/152362) while in subpopulation NFE AF = 0.000588 (40/68028). AF 95% confidence interval is 0.000444. There are 0 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 80 AD gene.

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.1280A>G	p.Lys427Arg	missense	Exon 13 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.1280A>G	p.Lys427Arg	missense	Exon 13 of 29	ENSP00000354720.5	Q9UQE7
	SMC3	ENST00000918257.1		c.1304A>G	p.Lys435Arg	missense	Exon 13 of 29	ENSP00000588316.1
	SMC3	ENST00000966376.1		c.1298A>G	p.Lys433Arg	missense	Exon 13 of 29	ENSP00000636435.1

Frequencies

GnomAD3 genomes AF: 0.000525 AC: 80 AN: 152244 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000558 AC: 140 AN: 251006 AF XY: 0.000611

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.000537

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000363 AC: 531 AN: 1461102 Hom.: 0 Cov.: 32 AF XY: 0.000366 AC XY: 266 AN XY: 726924

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.000537 AC: 24 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 45 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86212

European-Finnish (FIN) AF: 0.00256 AC: 137 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5574

European-Non Finnish (NFE) AF: 0.000270 AC: 300 AN: 1111694

Other (OTH) AF: 0.000398 AC: 24 AN: 60326

GnomAD4 genome AF: 0.000525 AC: 80 AN: 152362 Hom.: 0 Cov.: 32 AF XY: 0.000617 AC XY: 46 AN XY: 74506

African (AFR) AF: 0.0000481 AC: 2 AN: 41588

American (AMR) AF: 0.000261 AC: 4 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000869 Hom.: 0

Bravo AF: 0.000249

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000610 AC: 74

EpiCase AF: 0.000382

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Cornelia de Lange syndrome 3 (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	SMC3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.095
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-0.34	N
PhyloP100		8.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.28
Sift	Benign	0.48	T
Sift4G	Benign	0.52	T
Polyphen		0.042	B
Vest4		0.58
MVP		0.86
MPC		0.91
ClinPred		0.049	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.14
gMVP		0.67
Mutation Taster		=89/11	polymorphism

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: rs142524280; hg19: chr10-112344129;