10-110600347-A-G

Variant names:

• chr10-110600347-A-G
• rs3737292
• NM_005445.4:c.2428-92A>G

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.2428-92A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 749,804 control chromosomes in the GnomAD database, including 8,300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1243 hom., cov: 32)
  • Exomes 𝑓: 0.14 (7057 hom.)
• Consequence: SMC3 NM_005445.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.14
• Publications: 4 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=-0.87).
• BP6: Variant 10-110600347-A-G is Benign according to our data. Variant chr10-110600347-A-G is described in ClinVar as [Benign]. Clinvar id is 1271114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC3	NM_005445.4	c.2428-92A>G		intron_variant	Intron 21 of 28	ENST00000361804.5	NP_005436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC3	ENST00000361804.5	c.2428-92A>G		intron_variant	Intron 21 of 28	1	NM_005445.4	ENSP00000354720.5

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17916 AN: 152158 Hom.: 1239 Cov.: 32

Gnomad AFR AF: 0.0829

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.132

GnomAD4 exome AF: 0.140 AC: 83517 AN: 597528 Hom.: 7057 AF XY: 0.141 AC XY: 45777 AN XY: 325022

African (AFR) AF: 0.0845 AC: 1328 AN: 15708

American (AMR) AF: 0.243 AC: 8493 AN: 34958

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 2380 AN: 19204

East Asian (EAS) AF: 0.302 AC: 10773 AN: 35640

South Asian (SAS) AF: 0.185 AC: 11597 AN: 62714

European-Finnish (FIN) AF: 0.135 AC: 6962 AN: 51716

Middle Eastern (MID) AF: 0.159 AC: 406 AN: 2550

European-Non Finnish (NFE) AF: 0.109 AC: 37534 AN: 343658

Other (OTH) AF: 0.129 AC: 4044 AN: 31380

GnomAD4 genome AF: 0.118 AC: 17940 AN: 152276 Hom.: 1243 Cov.: 32 AF XY: 0.123 AC XY: 9137 AN XY: 74442

African (AFR) AF: 0.0830 AC: 3452 AN: 41574

American (AMR) AF: 0.175 AC: 2680 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 403 AN: 3472

East Asian (EAS) AF: 0.262 AC: 1356 AN: 5180

South Asian (SAS) AF: 0.184 AC: 890 AN: 4828

European-Finnish (FIN) AF: 0.136 AC: 1440 AN: 10598

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7342 AN: 68022

Other (OTH) AF: 0.133 AC: 280 AN: 2108

Alfa AF: 0.112 Hom.: 492

Bravo AF: 0.120

Asia WGS AF: 0.215 AC: 745 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.0
DANN	Benign	0.47
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3737292; hg19: chr10-112360105;