NM_005445.4:c.-99C>G

Variant names:

• chr10-110567718-C-G
• rs148267784
• NM_005445.4:c.-99C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005445.4(SMC3):​c.-99C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000077 in 1,299,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: SMC3 NM_005445.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.201
• 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: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005445.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC3	NM_005445.4	MANE Select	c.-99C>G		5_prime_UTR	Exon 1 of 29	NP_005436.1	Q9UQE7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC3	ENST00000361804.5	TSL:1 MANE Select	c.-99C>G		5_prime_UTR	Exon 1 of 29	ENSP00000354720.5	Q9UQE7
	SMC3	ENST00000918257.1		c.-99C>G		5_prime_UTR	Exon 1 of 29	ENSP00000588316.1
	SMC3	ENST00000966376.1		c.-99C>G		5_prime_UTR	Exon 1 of 29	ENSP00000636435.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.70e-7 AC: 1 AN: 1299482 Hom.: 0 Cov.: 18 AF XY: 0.00000153 AC XY: 1 AN XY: 653132

African (AFR) AF: 0.00 AC: 0 AN: 30136

American (AMR) AF: 0.00 AC: 0 AN: 42182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24248

East Asian (EAS) AF: 0.00 AC: 0 AN: 38720

South Asian (SAS) AF: 0.00 AC: 0 AN: 81726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51646

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4560

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 971620

Other (OTH) AF: 0.00 AC: 0 AN: 54644

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.80
PhyloP100		0.20
PromoterAI		-0.15	Neutral

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: rs148267784; hg19: chr10-112327476;