6-33200322-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_021976.5(RXRB):c.155C>G(p.Ala52Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000023 in 1,564,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: RXRB NM_021976.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45

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]

SLC39A7 (HGNC:4927): (solute carrier family 39 member 7) The protein encoded by this gene transports zinc from the Golgi and endoplasmic reticulum to the cytoplasm. This transport may be important for activation of tyrosine kinases, some of which could be involved in cancer progression. Therefore, modulation of the encoded protein could be useful as a therapeutic agent against cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RXRB
• BP4: Computational evidence support a benign effect (MetaRNN=0.11975163).
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RXRB	NM_021976.5	c.155C>G	p.Ala52Gly	missense_variant	1/10	ENST00000374680.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RXRB	ENST00000374680.4	c.155C>G	p.Ala52Gly	missense_variant	1/10	1	NM_021976.5	P4
RXRB	ENST00000374685.8	c.155C>G	p.Ala52Gly	missense_variant	1/10	1		A1
SLC39A7	ENST00000698677.1	n.18G>C		non_coding_transcript_exon_variant	1/6
RXRB	ENST00000483281.5	c.155C>G	p.Ala52Gly	missense_variant, NMD_transcript_variant	1/9	5

Frequencies

GnomAD3 genomes AF: 0.0000790 AC: 12 AN: 151940 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.0000589

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000276 AC: 5 AN: 181244 Hom.: 0 AF XY: 0.0000495 AC XY: 5 AN XY: 101046

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000339

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000721

Gnomad SAS exome AF: 0.0000385

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000259

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000170 AC: 24 AN: 1412836 Hom.: 0 Cov.: 31 AF XY: 0.0000214 AC XY: 15 AN XY: 700760

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000148

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000269

Gnomad4 SAS exome AF: 0.0000487

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000918

Gnomad4 OTH exome AF: 0.0000513

GnomAD4 genome AF: 0.0000790 AC: 12 AN: 151940 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74198

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000140

ExAC AF: 0.00000938 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2023

The c.155C>G (p.A52G) alteration is located in exon 1 (coding exon 1) of the RXRB gene. This alteration results from a C to G substitution at nucleotide position 155, causing the alanine (A) at amino acid position 52 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.078
FATHMM_MKL	Benign	0.17	N
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	-0.34	N;N
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.16	N;N
REVEL	Benign	0.27
Sift	Uncertain	0.026	D;D
Sift4G	Benign	0.11	T;T
Polyphen		0.14	.;B
Vest4		0.27
MutPred		0.36		Loss of stability (P = 0.0215);Loss of stability (P = 0.0215);
MVP		0.26
MPC		0.45
ClinPred		0.16	T
GERP RS		3.9
Varity_R		0.093
gMVP		0.12

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

LitVar

Other links and lift over

dbSNP: rs752973611; hg19: chr6-33168099;