chr8-116852713-TA-T

Variant names:

• chr8-116852713-TA-T
• rs369816312
• NM_006265.3:c.1162-6delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_006265.3(RAD21):​c.1162-6delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0939 in 1,058,964 control chromosomes in the GnomAD database, including 161 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (92 hom., cov: 31)
  • Exomes 𝑓: 0.10 (69 hom.)
• Consequence: RAD21 NM_006265.3 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.189
• Publications: 3 publications found

Genes affected

RAD21 (HGNC:9811): (RAD21 cohesin complex component) The protein encoded by this gene is highly similar to the gene product of Schizosaccharomyces pombe rad21, a gene involved in the repair of DNA double-strand breaks, as well as in chromatid cohesion during mitosis. This protein is a nuclear phospho-protein, which becomes hyperphosphorylated in cell cycle M phase. The highly regulated association of this protein with mitotic chromatin specifically at the centromere region suggests its role in sister chromatid cohesion in mitotic cells. [provided by RefSeq, Jul 2008]

RAD21 Gene-Disease associations (from GenCC):

• Cornelia de Lange syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Cornelia de Lange syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Mungan syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 8-116852713-TA-T is Benign according to our data. Variant chr8-116852713-TA-T is described in ClinVar as Benign. ClinVar VariationId is 211992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD21	NM_006265.3	c.1162-6delT		splice_region_variant, intron_variant	Intron 9 of 13	ENST00000297338.7	NP_006256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD21	ENST00000297338.7	c.1162-6delT		splice_region_variant, intron_variant	Intron 9 of 13	1	NM_006265.3	ENSP00000297338.2

Frequencies

GnomAD3 genomes AF: 0.0346 AC: 4671 AN: 135186 Hom.: 91 Cov.: 31

Gnomad AFR AF: 0.0557

Gnomad AMI AF: 0.0667

Gnomad AMR AF: 0.0263

Gnomad ASJ AF: 0.0621

Gnomad EAS AF: 0.00360

Gnomad SAS AF: 0.0368

Gnomad FIN AF: 0.0218

Gnomad MID AF: 0.0880

Gnomad NFE AF: 0.0252

Gnomad OTH AF: 0.0400

GnomAD2 exomes AF: 0.145 AC: 12658 AN: 87152 AF XY: 0.154

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.245

Gnomad EAS exome AF: 0.0996

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.168

GnomAD4 exome AF: 0.103 AC: 94742 AN: 923738 Hom.: 69 Cov.: 2 AF XY: 0.104 AC XY: 47384 AN XY: 454688

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.118 AC: 2404 AN: 20324

American (AMR) AF: 0.111 AC: 1970 AN: 17670

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 2303 AN: 15040

East Asian (EAS) AF: 0.0821 AC: 1975 AN: 24060

South Asian (SAS) AF: 0.132 AC: 5369 AN: 40538

European-Finnish (FIN) AF: 0.0981 AC: 3277 AN: 33418

Middle Eastern (MID) AF: 0.131 AC: 470 AN: 3600

European-Non Finnish (NFE) AF: 0.0995 AC: 72741 AN: 731316

Other (OTH) AF: 0.112 AC: 4233 AN: 37772

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0346 AC: 4680 AN: 135226 Hom.: 92 Cov.: 31 AF XY: 0.0348 AC XY: 2271 AN XY: 65212

African (AFR) AF: 0.0558 AC: 2072 AN: 37140

American (AMR) AF: 0.0262 AC: 353 AN: 13480

Ashkenazi Jewish (ASJ) AF: 0.0621 AC: 201 AN: 3238

East Asian (EAS) AF: 0.00361 AC: 17 AN: 4708

South Asian (SAS) AF: 0.0370 AC: 157 AN: 4248

European-Finnish (FIN) AF: 0.0218 AC: 164 AN: 7532

Middle Eastern (MID) AF: 0.0885 AC: 23 AN: 260

European-Non Finnish (NFE) AF: 0.0252 AC: 1558 AN: 61882

Other (OTH) AF: 0.0414 AC: 78 AN: 1884

Alfa AF: 0.00897 Hom.: 1

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Sep 26, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 08, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19
Mutation Taster		=100/0	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: rs369816312; hg19: chr8-117864952;