rs79912955

Variant names:

• chr10-110584175-T-G
• rs79912955
• NM_005445.4:c.1092-8T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005445.4(SMC3):​c.1092-8T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,613,310 control chromosomes in the GnomAD database, including 36 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (16 hom.)
• Consequence: SMC3 NM_005445.4 splice_region, intron
• Scores: Splicing: ADA: 0.009899
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.44
• Publications: 3 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: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 10-110584175-T-G is Benign according to our data. Variant chr10-110584175-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.009 (1371/152350) while in subpopulation AFR AF = 0.03 (1247/41584). AF 95% confidence interval is 0.0286. There are 20 homozygotes in GnomAd4. There are 630 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1371 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.1092-8T>G		splice_region 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.1092-8T>G		splice_region intron	N/A	ENSP00000354720.5	Q9UQE7
	SMC3	ENST00000918257.1		c.1116-8T>G		splice_region intron	N/A	ENSP00000588316.1
	SMC3	ENST00000966376.1		c.1110-8T>G		splice_region intron	N/A	ENSP00000636435.1

Frequencies

GnomAD3 genomes AF: 0.00899 AC: 1368 AN: 152232 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0300

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00264 AC: 662 AN: 251142 AF XY: 0.00206

Gnomad AFR exome AF: 0.0302

Gnomad AMR exome AF: 0.00280

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00125

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00105 AC: 1528 AN: 1460960 Hom.: 16 Cov.: 32 AF XY: 0.000944 AC XY: 686 AN XY: 726836

African (AFR) AF: 0.0307 AC: 1028 AN: 33466

American (AMR) AF: 0.00309 AC: 138 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26124

East Asian (EAS) AF: 0.000857 AC: 34 AN: 39658

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86242

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53418

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.000139 AC: 154 AN: 1111194

Other (OTH) AF: 0.00220 AC: 133 AN: 60366

GnomAD4 genome AF: 0.00900 AC: 1371 AN: 152350 Hom.: 20 Cov.: 32 AF XY: 0.00846 AC XY: 630 AN XY: 74508

African (AFR) AF: 0.0300 AC: 1247 AN: 41584

American (AMR) AF: 0.00516 AC: 79 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68038

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00518 Hom.: 1

Bravo AF: 0.0109

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.53
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0099
dbscSNV1_RF	Benign	0.23
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: rs79912955; hg19: chr10-112343933;