10-110569080-C-G

Variant names:

• chr10-110569080-C-G
• rs4917577
• NM_005445.4:c.91+67C>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.91+67C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 1,041,970 control chromosomes in the GnomAD database, including 520,488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (75870 hom., cov: 32)
  • Exomes 𝑓: 1.0 (444618 hom.)
• Consequence: SMC3 NM_005445.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.02
• Publications: 3 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=-0.92).
• BP6: Variant 10-110569080-C-G is Benign according to our data. Variant chr10-110569080-C-G is described in ClinVar as [Benign]. Clinvar id is 674950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC3	NM_005445.4	c.91+67C>G		intron_variant	Intron 2 of 28	ENST00000361804.5	NP_005436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC3	ENST00000361804.5	c.91+67C>G		intron_variant	Intron 2 of 28	1	NM_005445.4	ENSP00000354720.5

Frequencies

GnomAD3 genomes AF: 0.998 AC: 151935 AN: 152250 Hom.: 75810 Cov.: 32

Gnomad AFR AF: 0.993

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.999

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.998

GnomAD4 exome AF: 1.00 AC: 889418 AN: 889602 Hom.: 444618 AF XY: 1.00 AC XY: 466152 AN XY: 466232

African (AFR) AF: 0.993 AC: 22291 AN: 22442

American (AMR) AF: 1.00 AC: 43559 AN: 43572

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 22580 AN: 22580

East Asian (EAS) AF: 1.00 AC: 36990 AN: 36990

South Asian (SAS) AF: 1.00 AC: 73330 AN: 73330

European-Finnish (FIN) AF: 1.00 AC: 52322 AN: 52322

Middle Eastern (MID) AF: 1.00 AC: 4362 AN: 4362

European-Non Finnish (NFE) AF: 1.00 AC: 592490 AN: 592492

Other (OTH) AF: 1.00 AC: 41494 AN: 41512

GnomAD4 genome AF: 0.998 AC: 152054 AN: 152368 Hom.: 75870 Cov.: 32 AF XY: 0.998 AC XY: 74375 AN XY: 74514

African (AFR) AF: 0.993 AC: 41274 AN: 41574

American (AMR) AF: 0.999 AC: 15302 AN: 15310

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5186 AN: 5186

South Asian (SAS) AF: 1.00 AC: 4834 AN: 4834

European-Finnish (FIN) AF: 1.00 AC: 10624 AN: 10624

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68047 AN: 68048

Other (OTH) AF: 0.998 AC: 2109 AN: 2114

Alfa AF: 1.00 Hom.: 3365

Bravo AF: 0.998

Asia WGS AF: 1.00 AC: 3467 AN: 3468

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

- -

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.2
DANN	Benign	0.56
PhyloP100		-1.0
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: rs4917577; hg19: chr10-112328838;