10-110568767-CT-C

Variant names:

• chr10-110568767-CT-C
• rs35132779
• NM_005445.4:c.16-158delT

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.16-158delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00865 in 142,948 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0086 (7 hom., cov: 27)
• Consequence: SMC3 NM_005445.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.208
• 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 10-110568767-CT-C is Benign according to our data. Variant chr10-110568767-CT-C is described in ClinVar as [Likely_benign]. Clinvar id is 1209217.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00865 (1236/142948) while in subpopulation SAS AF = 0.0189 (86/4542). AF 95% confidence interval is 0.0157. There are 7 homozygotes in GnomAd4. There are 658 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1236 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC3	NM_005445.4	c.16-158delT		intron_variant	Intron 1 of 28	ENST00000361804.5	NP_005436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC3	ENST00000361804.5	c.16-170delT		intron_variant	Intron 1 of 28	1	NM_005445.4	ENSP00000354720.5

Frequencies

GnomAD3 genomes AF: 0.00861 AC: 1230 AN: 142896 Hom.: 7 Cov.: 27

Gnomad AFR AF: 0.0100

Gnomad AMI AF: 0.0802

Gnomad AMR AF: 0.00598

Gnomad ASJ AF: 0.00478

Gnomad EAS AF: 0.00120

Gnomad SAS AF: 0.0184

Gnomad FIN AF: 0.0208

Gnomad MID AF: 0.00685

Gnomad NFE AF: 0.00590

Gnomad OTH AF: 0.00668

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00865 AC: 1236 AN: 142948 Hom.: 7 Cov.: 27 AF XY: 0.00948 AC XY: 658 AN XY: 69382

African (AFR) AF: 0.0101 AC: 396 AN: 39154

American (AMR) AF: 0.00598 AC: 86 AN: 14392

Ashkenazi Jewish (ASJ) AF: 0.00478 AC: 16 AN: 3344

East Asian (EAS) AF: 0.00120 AC: 6 AN: 5004

South Asian (SAS) AF: 0.0189 AC: 86 AN: 4542

European-Finnish (FIN) AF: 0.0208 AC: 176 AN: 8474

Middle Eastern (MID) AF: 0.00735 AC: 2 AN: 272

European-Non Finnish (NFE) AF: 0.00590 AC: 383 AN: 64912

Other (OTH) AF: 0.00665 AC: 13 AN: 1956

Alfa AF: 0.00177 Hom.: 57

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 19, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.21
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: rs35132779; hg19: chr10-112328525; COSMIC: COSV62422593;