chr1-165419909-C-A

Position:

• chr1-165419909-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006917.5(RXRG):​c.403G>T​(p.Val135Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RXRG NM_006917.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46

Genes affected

RXRG (HGNC:10479): (retinoid X receptor gamma) This gene encodes a member of the retinoid X receptor (RXR) family of nuclear receptors which are involved in mediating the antiproliferative effects of retinoic acid (RA). This receptor forms dimers with the retinoic acid, thyroid hormone, and vitamin D receptors, increasing both DNA binding and transcriptional function on their respective response elements. This gene is expressed at significantly lower levels in non-small cell lung cancer cells. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18479595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RXRG	NM_006917.5	c.403G>T	p.Val135Phe	missense_variant	3/10	ENST00000359842.10
RXRG	NM_001256570.2	c.34G>T	p.Val12Phe	missense_variant	4/11
RXRG	NM_001256571.2	c.34G>T	p.Val12Phe	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RXRG	ENST00000359842.10	c.403G>T	p.Val135Phe	missense_variant	3/10	1	NM_006917.5	P1
RXRG	ENST00000619224.1	c.34G>T	p.Val12Phe	missense_variant	4/11	1
RXRG	ENST00000470566.1	n.328G>T		non_coding_transcript_exon_variant	2/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Dec 27, 2023

The c.403G>T (p.V135F) alteration is located in exon 3 (coding exon 3) of the RXRG gene. This alteration results from a G to T substitution at nucleotide position 403, causing the valine (V) at amino acid position 135 to be replaced by a phenylalanine (F). 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	0.16
BayesDel_addAF	Benign	-0.0067	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.066
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.37	N;.
MutationTaster	Benign	0.56	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.78	N;.
REVEL	Benign	0.21
Sift	Benign	0.089	T;.
Sift4G	Benign	0.52	T;T
Polyphen		0.17	B;.
Vest4		0.27
MutPred		0.30		Loss of ubiquitination at K136 (P = 0.0863);.;
MVP		0.30
MPC		0.85
ClinPred		0.73	D
GERP RS		4.3
Varity_R		0.12
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-165389146;