rs11815960

Variant names:

• chr10-110583358-A-G
• rs11815960
• NM_005445.4:c.805-26A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005445.4(SMC3):​c.805-26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.052 in 1,593,970 control chromosomes in the GnomAD database, including 3,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.092 (1103 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2347 hom.)
• Consequence: SMC3 NM_005445.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.452
• Publications: 6 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-110583358-A-G is Benign according to our data. Variant chr10-110583358-A-G is described in ClinVar as Benign. ClinVar VariationId is 1231960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

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.805-26A>G		intron	N/A	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.805-26A>G		intron	N/A	ENSP00000354720.5	Q9UQE7
	SMC3	ENST00000918257.1		c.805-26A>G		intron	N/A	ENSP00000588316.1
	SMC3	ENST00000966376.1		c.823-26A>G		intron	N/A	ENSP00000636435.1

Frequencies

GnomAD3 genomes AF: 0.0914 AC: 13900 AN: 152066 Hom.: 1101 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0547

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0364

Gnomad FIN AF: 0.0505

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0443

Gnomad OTH AF: 0.0956

GnomAD2 exomes AF: 0.0512 AC: 12756 AN: 249190 AF XY: 0.0491

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.0357

Gnomad ASJ exome AF: 0.0416

Gnomad EAS exome AF: 0.000382

Gnomad FIN exome AF: 0.0480

Gnomad NFE exome AF: 0.0461

Gnomad OTH exome AF: 0.0574

GnomAD4 exome AF: 0.0478 AC: 68917 AN: 1441786 Hom.: 2347 Cov.: 30 AF XY: 0.0471 AC XY: 33876 AN XY: 718490

African (AFR) AF: 0.223 AC: 7335 AN: 32826

American (AMR) AF: 0.0387 AC: 1725 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.0401 AC: 1044 AN: 26006

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39582

South Asian (SAS) AF: 0.0381 AC: 3265 AN: 85634

European-Finnish (FIN) AF: 0.0482 AC: 2555 AN: 53010

Middle Eastern (MID) AF: 0.0870 AC: 401 AN: 4610

European-Non Finnish (NFE) AF: 0.0449 AC: 49219 AN: 1095850

Other (OTH) AF: 0.0564 AC: 3367 AN: 59672

GnomAD4 genome AF: 0.0915 AC: 13926 AN: 152184 Hom.: 1103 Cov.: 32 AF XY: 0.0895 AC XY: 6657 AN XY: 74416

African (AFR) AF: 0.216 AC: 8961 AN: 41488

American (AMR) AF: 0.0546 AC: 835 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0435 AC: 151 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0366 AC: 177 AN: 4830

European-Finnish (FIN) AF: 0.0505 AC: 535 AN: 10586

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0443 AC: 3010 AN: 68008

Other (OTH) AF: 0.0946 AC: 200 AN: 2114

Alfa AF: 0.0690 Hom.: 235

Bravo AF: 0.0979

Asia WGS AF: 0.0310 AC: 107 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.2
DANN	Benign	0.49
PhyloP100		-0.45
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs11815960; hg19: chr10-112343116; COSMIC: COSV62419781;