Genetic Variant NM_021976.5:c.971G>A (chr6-33196456-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_021976.5(RXRB):c.971G>A(p.Gly324Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000484 in 1,612,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

RXRB
NM_021976.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.47

Publications

2 publications found

Variant links:

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]

RXRB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26492125).

BS2

High AC in GnomAd4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021976.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RXRB	NM_021976.5	MANE Select	c.971G>A	p.Gly324Glu	missense	Exon 5 of 10	NP_068811.1	Q5STP9
RXRB	NM_001270401.2		c.971G>A	p.Gly324Glu	missense	Exon 5 of 10	NP_001257330.1	A0A0S2Z570
RXRB	NM_001291989.2		c.401G>A	p.Gly134Glu	missense	Exon 4 of 9	NP_001278918.1	A0A0G2JKR7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RXRB	ENST00000374680.4	TSL:1 MANE Select	c.971G>A	p.Gly324Glu	missense	Exon 5 of 10	ENSP00000363812.3	P28702-1
RXRB	ENST00000374685.8	TSL:1	c.971G>A	p.Gly324Glu	missense	Exon 5 of 10	ENSP00000363817.4	P28702-3
RXRB	ENST00000865272.1		c.971G>A	p.Gly324Glu	missense	Exon 5 of 10	ENSP00000535331.1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000365

AC:

AN:

246394

AF XY:

0.0000521

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000633

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000466

AC:

AN:

1460684

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

726660

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52282

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000540

AC:

AN:

1111960

Other (OTH)

AF:

0.0000828

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000124

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000595

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.055

FATHMM_MKL

Uncertain

0.94

M_CAP

Benign

0.053

MetaRNN

Benign

0.26

MetaSVM

Uncertain

-0.087

MutationAssessor

Benign

0.34

PhyloP100

2.5

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.98

REVEL

Uncertain

0.51

Sift

Benign

0.38

Sift4G

Benign

1.0

Polyphen

0.13

Vest4

0.39

MVP

0.77

MPC

1.6

ClinPred

0.22

GERP RS

4.0

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.065

gMVP

0.12

Mutation Taster

=75/25

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over