X-53422829-C-T

Variant names:

• chrX-53422829-C-T
• rs186837286
• ENST00000329209:c.-181C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000329209(RIBC1):​c.-181C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0465 in 362,286 control chromosomes in the GnomAD database, including 405 homozygotes. There are 4,801 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (126 hom., 1375 hem., cov: 24)
  • Exomes 𝑓: 0.049 (279 hom. 3426 hem.)
• Consequence: RIBC1 ENST00000329209 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.333

Genes affected

RIBC1 (HGNC:26537): (RIB43A domain with coiled-coils 1)

SMC1A (HGNC:11111): (structural maintenance of chromosomes 1A) Proper cohesion of sister chromatids is a prerequisite for the correct segregation of chromosomes during cell division. The cohesin multiprotein complex is required for sister chromatid cohesion. This complex is composed partly of two structural maintenance of chromosomes (SMC) proteins, SMC3 and either SMC1B or the protein encoded by this gene. Most of the cohesin complexes dissociate from the chromosomes before mitosis, although those complexes at the kinetochore remain. Therefore, the encoded protein is thought to be an important part of functional kinetochores. In addition, this protein interacts with BRCA1 and is phosphorylated by ATM, indicating a potential role for this protein in DNA repair. This gene, which belongs to the SMC gene family, is located in an area of the X-chromosome that escapes X inactivation. Mutations in this gene result in Cornelia de Lange syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant X-53422829-C-T is Benign according to our data. Variant chrX-53422829-C-T is described in ClinVar as [Benign]. Clinvar id is 1226124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC1A	NM_006306.4	c.-229G>A		upstream_gene_variant		ENST00000322213.9	NP_006297.2
RIBC1	NM_001031745.5	c.-265C>T		upstream_gene_variant		ENST00000375327.6	NP_001026915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC1A	ENST00000322213.9	c.-229G>A		upstream_gene_variant		1	NM_006306.4	ENSP00000323421.3
RIBC1	ENST00000375327.6	c.-265C>T		upstream_gene_variant		1	NM_001031745.5	ENSP00000364476.3

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 4680 AN: 112917 Hom.: 126 Cov.: 24 AF XY: 0.0393 AC XY: 1376 AN XY: 35055

Gnomad AFR AF: 0.00880

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.0261

Gnomad ASJ AF: 0.0226

Gnomad EAS AF: 0.00112

Gnomad SAS AF: 0.00610

Gnomad FIN AF: 0.0637

Gnomad MID AF: 0.0167

Gnomad NFE AF: 0.0653

Gnomad OTH AF: 0.0361

GnomAD4 exome AF: 0.0488 AC: 12179 AN: 249318 Hom.: 279 Cov.: 0 AF XY: 0.0457 AC XY: 3426 AN XY: 74946

Gnomad4 AFR exome AF: 0.00946

Gnomad4 AMR exome AF: 0.0216

Gnomad4 ASJ exome AF: 0.0250

Gnomad4 EAS exome AF: 0.0000630

Gnomad4 SAS exome AF: 0.00776

Gnomad4 FIN exome AF: 0.0611

Gnomad4 NFE exome AF: 0.0665

Gnomad4 OTH exome AF: 0.0476

GnomAD4 genome AF: 0.0414 AC: 4678 AN: 112968 Hom.: 126 Cov.: 24 AF XY: 0.0392 AC XY: 1375 AN XY: 35116

Gnomad4 AFR AF: 0.00878

Gnomad4 AMR AF: 0.0260

Gnomad4 ASJ AF: 0.0226

Gnomad4 EAS AF: 0.00112

Gnomad4 SAS AF: 0.00611

Gnomad4 FIN AF: 0.0637

Gnomad4 NFE AF: 0.0652

Gnomad4 OTH AF: 0.0357

Alfa AF: 0.0482 Hom.: 267

Bravo AF: 0.0389

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 15, 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	-0.76
CADD	Benign	4.8
DANN	Benign	0.89

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs186837286; hg19: chrX-53449778;