6-33194833-G-GGGTGGA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_021976.5(RXRB):c.1455-5_1455-4insTCCACC variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00201 in 1,612,780 control chromosomes in the GnomAD database, including 230 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (206 hom.)
• Consequence: RXRB NM_021976.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.10

Genes affected

RXRB (HGNC:10478): (retinoid X receptor beta) This gene encodes a member of the retinoid X receptor (RXR) family of nuclear receptors which are involved in mediating the effects of retinoic acid (RA). The encoded protein forms homodimers with the retinoic acid, thyroid hormone, and vitamin D receptors, increasing both DNA binding and transcriptional function on their respective response elements. This gene lies within the major histocompatibility complex (MHC) class II region on chromosome 6. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 6-33194833-G-GGGTGGA is Benign according to our data. Variant chr6-33194833-G-GGGTGGA is described in ClinVar as [Benign]. Clinvar id is 779906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00294 (448/152326) while in subpopulation EAS AF= 0.0519 (269/5184). AF 95% confidence interval is 0.0468. There are 24 homozygotes in gnomad4. There are 251 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 452 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RXRB	NM_021976.5	c.1455-5_1455-4insTCCACC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000374680.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RXRB	ENST00000374680.4	c.1455-5_1455-4insTCCACC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_021976.5	P4
RXRB	ENST00000374685.8	c.1467-5_1467-4insTCCACC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		A1
RXRB	ENST00000483281.5	c.*967-5_*967-4insTCCACC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5
RXRB	ENST00000483821.1	n.417-5_417-4insTCCACC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 452 AN: 152208 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0523

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00521 AC: 1283 AN: 246186 Hom.: 39 AF XY: 0.00517 AC XY: 694 AN XY: 134206

Gnomad AFR exome AF: 0.000794

Gnomad AMR exome AF: 0.000639

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0510

Gnomad SAS exome AF: 0.00911

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000272

Gnomad OTH exome AF: 0.00611

GnomAD4 exome AF: 0.00192 AC: 2801 AN: 1460454 Hom.: 206 Cov.: 32 AF XY: 0.00199 AC XY: 1446 AN XY: 726516

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0268

Gnomad4 SAS exome AF: 0.00963

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0140

GnomAD4 genome AF: 0.00294 AC: 448 AN: 152326 Hom.: 24 Cov.: 32 AF XY: 0.00337 AC XY: 251 AN XY: 74490

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0519

Gnomad4 SAS AF: 0.0230

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00158 Hom.: 3

Asia WGS AF: 0.0500 AC: 175 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RXRB-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs143154990; hg19: chr6-33162610;