rs147070453

Variant names:

• chr10-110589856-TTTAAAA-T
• rs147070453
• NM_005445.4:c.1410-30_1410-25delATTAAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_005445.4(SMC3):​c.1410-30_1410-25delATTAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,592,840 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (5 hom.)
• Consequence: SMC3 NM_005445.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.73
• 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: 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 -10 ACMG points.

• BP6: Variant 10-110589856-TTTAAAA-T is Benign according to our data. Variant chr10-110589856-TTTAAAA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 259766.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00153 (233/152346) while in subpopulation AMR AF = 0.0034 (52/15296). AF 95% confidence interval is 0.00266. There are 0 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 233 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC3	NM_005445.4	c.1410-30_1410-25delATTAAA		intron_variant	Intron 14 of 28	ENST00000361804.5	NP_005436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC3	ENST00000361804.5	c.1410-35_1410-30delTTAAAA		intron_variant	Intron 14 of 28	1	NM_005445.4	ENSP00000354720.5

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 233 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00166 AC: 415 AN: 250138 AF XY: 0.00162

Gnomad AFR exome AF: 0.000444

Gnomad AMR exome AF: 0.000695

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.00318

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.00276 AC: 3978 AN: 1440494 Hom.: 5 AF XY: 0.00261 AC XY: 1871 AN XY: 718048

African (AFR) AF: 0.000453 AC: 15 AN: 33086

American (AMR) AF: 0.000984 AC: 44 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25974

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.000198 AC: 17 AN: 85752

European-Finnish (FIN) AF: 0.000825 AC: 44 AN: 53304

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5668

European-Non Finnish (NFE) AF: 0.00342 AC: 3732 AN: 1092800

Other (OTH) AF: 0.00208 AC: 124 AN: 59672

GnomAD4 genome AF: 0.00153 AC: 233 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.00146 AC XY: 109 AN XY: 74504

African (AFR) AF: 0.000529 AC: 22 AN: 41580

American (AMR) AF: 0.00340 AC: 52 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

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

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

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00215 AC: 146 AN: 68032

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00149 Hom.: 0

Bravo AF: 0.00188

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs147070453; hg19: chr10-112349614;