10-110590121-A-G

Variant names:

• chr10-110590121-A-G
• rs3737294
• NM_005445.4:c.1509+130A>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.1509+130A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 751,268 control chromosomes in the GnomAD database, including 15,899 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4666 hom., cov: 33)
  • Exomes 𝑓: 0.18 (11233 hom.)
• Consequence: SMC3 NM_005445.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.17
• Publications: 7 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=-0.82).
• BP6: Variant 10-110590121-A-G is Benign according to our data. Variant chr10-110590121-A-G is described in ClinVar as [Benign]. Clinvar id is 1245805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC3	NM_005445.4	c.1509+130A>G		intron_variant	Intron 15 of 28	ENST00000361804.5	NP_005436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC3	ENST00000361804.5	c.1509+130A>G		intron_variant	Intron 15 of 28	1	NM_005445.4	ENSP00000354720.5

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34619 AN: 152032 Hom.: 4646 Cov.: 33

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.235

GnomAD4 exome AF: 0.182 AC: 109249 AN: 599118 Hom.: 11233 AF XY: 0.183 AC XY: 58313 AN XY: 318138

African (AFR) AF: 0.369 AC: 5518 AN: 14938

American (AMR) AF: 0.279 AC: 7166 AN: 25722

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 2941 AN: 18268

East Asian (EAS) AF: 0.303 AC: 9718 AN: 32048

South Asian (SAS) AF: 0.225 AC: 12830 AN: 56932

European-Finnish (FIN) AF: 0.183 AC: 8323 AN: 45438

Middle Eastern (MID) AF: 0.265 AC: 1053 AN: 3978

European-Non Finnish (NFE) AF: 0.150 AC: 55715 AN: 370532

Other (OTH) AF: 0.191 AC: 5985 AN: 31262

GnomAD4 genome AF: 0.228 AC: 34698 AN: 152150 Hom.: 4666 Cov.: 33 AF XY: 0.230 AC XY: 17127 AN XY: 74402

African (AFR) AF: 0.366 AC: 15203 AN: 41490

American (AMR) AF: 0.239 AC: 3656 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 545 AN: 3466

East Asian (EAS) AF: 0.257 AC: 1330 AN: 5178

South Asian (SAS) AF: 0.222 AC: 1070 AN: 4820

European-Finnish (FIN) AF: 0.186 AC: 1968 AN: 10592

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10275 AN: 68002

Other (OTH) AF: 0.235 AC: 497 AN: 2114

Alfa AF: 0.183 Hom.: 8187

Bravo AF: 0.240

Asia WGS AF: 0.257 AC: 892 AN: 3476

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	-0.82
CADD	Benign	13
DANN	Benign	0.74
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs3737294; hg19: chr10-112349879;