chr9-134409102-T-C

Variant names:

• chr9-134409102-T-C
• rs778077188
• NM_002957.6:c.593T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP2 PP3 BS2

The NM_002957.6(RXRA):​c.593T>C​(p.Met198Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,438,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: RXRA NM_002957.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.93
• Publications: 1 publications found

Genes affected

RXRA (HGNC:10477): (retinoid X receptor alpha) Retinoid X receptors (RXRs) and retinoic acid receptors (RARs) are nuclear receptors that mediate the biological effects of retinoids by their involvement in retinoic acid-mediated gene activation. These receptors function as transcription factors by binding as homodimers or heterodimers to specific sequences in the promoters of target genes. The protein encoded by this gene is a member of the steroid and thyroid hormone receptor superfamily of transcriptional regulators. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

RXRA Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.9681 (below the threshold of 3.09). Trascript score misZ: 3.5958 (above the threshold of 3.09).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002957.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RXRA	NM_002957.6	MANE Select	c.593T>C	p.Met198Thr	missense	Exon 4 of 10	NP_002948.1	P19793-1
	RXRA	NM_001291920.2		c.512T>C	p.Met171Thr	missense	Exon 4 of 10	NP_001278849.1	A0A5F9ZHH6
	RXRA	NM_001291921.2		c.302T>C	p.Met101Thr	missense	Exon 3 of 9	NP_001278850.1	P19793-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RXRA	ENST00000481739.2	TSL:1 MANE Select	c.593T>C	p.Met198Thr	missense	Exon 4 of 10	ENSP00000419692.1	P19793-1
	RXRA	ENST00000672570.1		c.512T>C	p.Met171Thr	missense	Exon 4 of 10	ENSP00000500402.1	A0A5F9ZHH6
	RXRA	ENST00000356384.4	TSL:5	n.1003T>C		non_coding_transcript_exon	Exon 6 of 12

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000867 AC: 2 AN: 230766 AF XY: 0.00000796

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: 0.00000951

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000118 AC: 17 AN: 1438386 Hom.: 0 Cov.: 31 AF XY: 0.0000168 AC XY: 12 AN XY: 714396

African (AFR) AF: 0.00 AC: 0 AN: 32364

American (AMR) AF: 0.00 AC: 0 AN: 41452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25234

East Asian (EAS) AF: 0.00 AC: 0 AN: 38266

South Asian (SAS) AF: 0.0000955 AC: 8 AN: 83780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 0.00000818 AC: 9 AN: 1099818

Other (OTH) AF: 0.00 AC: 0 AN: 59444

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	1.7	L
PhyloP100		5.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.82
Sift	Benign	0.18	T
Sift4G	Benign	0.27	T
Polyphen		0.29	B
Vest4		0.87
MutPred		0.60		Loss of catalytic residue at M198 (P = 0.0287)
MVP		0.96
MPC		1.2
ClinPred		0.75	D
GERP RS		4.6
Varity_R		0.75
gMVP		0.94
Mutation Taster		=17/83	disease causing

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: rs778077188; hg19: chr9-137300948;