rs11195199

Variant names:

• chr10-110583833-G-A
• rs11195199
• NM_005445.4:c.970-8G>A

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.970-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,608,740 control chromosomes in the GnomAD database, including 12,725 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1221 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11504 hom.)
• Consequence: SMC3 NM_005445.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001165
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.25
• Publications: 15 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: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 10-110583833-G-A is Benign according to our data. Variant chr10-110583833-G-A is described in ClinVar as Benign. ClinVar VariationId is 159992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.252 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC3	NM_005445.4	MANE Select	c.970-8G>A		splice_region intron	N/A	NP_005436.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC3	ENST00000361804.5	TSL:1 MANE Select	c.970-8G>A		splice_region intron	N/A	ENSP00000354720.5
	SMC3	ENST00000684988.1		n.1387G>A		non_coding_transcript_exon	Exon 11 of 25
	SMC3	ENST00000687823.1		n.884-8G>A		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17725 AN: 151818 Hom.: 1217 Cov.: 32

Gnomad AFR AF: 0.0827

Gnomad AMI AF: 0.0538

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.130

GnomAD2 exomes AF: 0.151 AC: 37473 AN: 248774 AF XY: 0.148

Gnomad AFR exome AF: 0.0836

Gnomad AMR exome AF: 0.261

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.247

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.115 AC: 167743 AN: 1456804 Hom.: 11504 Cov.: 32 AF XY: 0.117 AC XY: 84795 AN XY: 724704

African (AFR) AF: 0.0808 AC: 2689 AN: 33274

American (AMR) AF: 0.248 AC: 10983 AN: 44252

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3098 AN: 26034

East Asian (EAS) AF: 0.298 AC: 11761 AN: 39492

South Asian (SAS) AF: 0.177 AC: 15163 AN: 85472

European-Finnish (FIN) AF: 0.134 AC: 7146 AN: 53176

Middle Eastern (MID) AF: 0.163 AC: 937 AN: 5746

European-Non Finnish (NFE) AF: 0.0980 AC: 108666 AN: 1109190

Other (OTH) AF: 0.121 AC: 7300 AN: 60168

GnomAD4 genome AF: 0.117 AC: 17751 AN: 151936 Hom.: 1221 Cov.: 32 AF XY: 0.122 AC XY: 9055 AN XY: 74276

African (AFR) AF: 0.0828 AC: 3432 AN: 41462

American (AMR) AF: 0.175 AC: 2672 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 391 AN: 3470

East Asian (EAS) AF: 0.263 AC: 1361 AN: 5172

South Asian (SAS) AF: 0.179 AC: 860 AN: 4810

European-Finnish (FIN) AF: 0.136 AC: 1433 AN: 10518

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7232 AN: 67920

Other (OTH) AF: 0.131 AC: 276 AN: 2108

Alfa AF: 0.108 Hom.: 1152

Bravo AF: 0.119

Asia WGS AF: 0.213 AC: 740 AN: 3478

EpiCase AF: 0.104

EpiControl AF: 0.109

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.0
DANN	Benign	0.42
PhyloP100		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0
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: rs11195199; hg19: chr10-112343591; COSMIC: COSV62418757; COSMIC: COSV62418757;