rs148267784

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr10-110567718-C-A
• chr10-110567718-C-G
• chr10-110567718-C-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_005445.4(SMC3):​c.-99C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 1,451,596 control chromosomes in the GnomAD database, including 278 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (21 hom., cov: 34)
  • Exomes 𝑓: 0.017 (257 hom.)
• Consequence: SMC3 NM_005445.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.201
• Publications: 1 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 10-110567718-C-A is Benign according to our data. Variant chr10-110567718-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 298759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.014 (2133/152338) while in subpopulation AMR AF = 0.041 (628/15304). AF 95% confidence interval is 0.0384. There are 21 homozygotes in GnomAd4. There are 1067 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2133 AD gene.

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>A		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>A		5_prime_UTR	Exon 1 of 29	ENSP00000354720.5	Q9UQE7
	SMC3	ENST00000918257.1		c.-99C>A		5_prime_UTR	Exon 1 of 29	ENSP00000588316.1
	SMC3	ENST00000966376.1		c.-99C>A		5_prime_UTR	Exon 1 of 29	ENSP00000636435.1

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2127 AN: 152220 Hom.: 21 Cov.: 34

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0408

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0192

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0164

Gnomad OTH AF: 0.0163

GnomAD4 exome AF: 0.0174 AC: 22670 AN: 1299258 Hom.: 257 Cov.: 18 AF XY: 0.0176 AC XY: 11473 AN XY: 653032

African (AFR) AF: 0.00421 AC: 127 AN: 30136

American (AMR) AF: 0.0441 AC: 1859 AN: 42176

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 415 AN: 24244

East Asian (EAS) AF: 0.000129 AC: 5 AN: 38720

South Asian (SAS) AF: 0.0220 AC: 1801 AN: 81724

European-Finnish (FIN) AF: 0.00558 AC: 288 AN: 51642

Middle Eastern (MID) AF: 0.0342 AC: 156 AN: 4558

European-Non Finnish (NFE) AF: 0.0176 AC: 17092 AN: 971420

Other (OTH) AF: 0.0170 AC: 927 AN: 54638

GnomAD4 genome AF: 0.0140 AC: 2133 AN: 152338 Hom.: 21 Cov.: 34 AF XY: 0.0143 AC XY: 1067 AN XY: 74488

African (AFR) AF: 0.00327 AC: 136 AN: 41590

American (AMR) AF: 0.0410 AC: 628 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5172

South Asian (SAS) AF: 0.0192 AC: 93 AN: 4834

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10630

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0164 AC: 1113 AN: 68018

Other (OTH) AF: 0.0166 AC: 35 AN: 2114

Alfa AF: 0.00368 Hom.: 0

Bravo AF: 0.0161

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cornelia de Lange syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	12
DANN	Benign	0.82
PhyloP100		0.20
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=300/0	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: rs148267784; hg19: chr10-112327476;