10-110600561-T-G

Variant names:

• chr10-110600561-T-G
• rs3818903
• NM_005445.4:c.2535+15T>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005445.4(SMC3):​c.2535+15T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000496 in 1,336,048 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00051 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (1 hom.)
• Consequence: SMC3 NM_005445.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.818
• Publications: 0 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: ClinGen, Orphanet
• Cornelia de Lange syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 10-110600561-T-G is Benign according to our data. Variant chr10-110600561-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159979.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000507 (77/151918) while in subpopulation EAS AF = 0.0139 (72/5180). AF 95% confidence interval is 0.0113. There are 1 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 77 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.2535+15T>G		intron	N/A	NP_005436.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC3	ENST00000361804.5	TSL:1 MANE Select	c.2535+15T>G		intron	N/A	ENSP00000354720.5
	SMC3	ENST00000918257.1		c.2559+15T>G		intron	N/A	ENSP00000588316.1
	SMC3	ENST00000966376.1		c.2553+15T>G		intron	N/A	ENSP00000636435.1

Frequencies

GnomAD3 genomes AF: 0.000507 AC: 77 AN: 151802 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0139

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00130 AC: 316 AN: 242718 AF XY: 0.00119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0178

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000851

GnomAD4 exome AF: 0.000495 AC: 586 AN: 1184130 Hom.: 1 Cov.: 17 AF XY: 0.000468 AC XY: 282 AN XY: 602446

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000365 AC: 1 AN: 27392

American (AMR) AF: 0.00 AC: 0 AN: 43434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24162

East Asian (EAS) AF: 0.0144 AC: 541 AN: 37642

South Asian (SAS) AF: 0.0000878 AC: 7 AN: 79682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5220

European-Non Finnish (NFE) AF: 0.0000116 AC: 10 AN: 862710

Other (OTH) AF: 0.000529 AC: 27 AN: 51042

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000507 AC: 77 AN: 151918 Hom.: 1 Cov.: 32 AF XY: 0.000619 AC XY: 46 AN XY: 74282

African (AFR) AF: 0.0000241 AC: 1 AN: 41478

American (AMR) AF: 0.000131 AC: 2 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0139 AC: 72 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67908

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000238 Hom.: 0

Bravo AF: 0.000771

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Cornelia de Lange syndrome 3 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.5
DANN	Benign	0.23
PhyloP100		0.82
Mutation Taster		=100/0	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: rs3818903; hg19: chr10-112360319;