chr12-53214587-G-T

Variant names:

• chr12-53214587-G-T
• rs745345035
• NM_000966.6:c.495C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000966.6(RARG):​c.495C>A​(p.Asn165Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RARG NM_000966.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.37
• Publications: 1 publications found

Genes affected

RARG (HGNC:9866): (retinoic acid receptor gamma) This gene encodes a retinoic acid receptor that belongs to the nuclear hormone receptor family. Retinoic acid receptors (RARs) act as ligand-dependent transcriptional regulators. When bound to ligands, RARs activate transcription by binding as heterodimers to the retinoic acid response elements (RARE) found in the promoter regions of the target genes. In their unbound form, RARs repress transcription of their target genes. RARs are involved in various biological processes, including limb bud development, skeletal growth, and matrix homeostasis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000966.6. 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
	RARG	NM_000966.6	MANE Select	c.495C>A	p.Asn165Lys	missense	Exon 6 of 10	NP_000957.1	A8K3H3
	RARG	NM_001042728.3		c.462C>A	p.Asn154Lys	missense	Exon 4 of 8	NP_001036193.1	P13631-2
	RARG	NM_001243732.2		c.429C>A	p.Asn143Lys	missense	Exon 3 of 7	NP_001230661.1	P13631-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARG	ENST00000425354.7	TSL:1 MANE Select	c.495C>A	p.Asn165Lys	missense	Exon 6 of 10	ENSP00000388510.2	P13631-1
	RARG	ENST00000338561.9	TSL:1	c.462C>A	p.Asn154Lys	missense	Exon 4 of 8	ENSP00000343698.5	P13631-2
	RARG	ENST00000394426.5	TSL:1	c.279C>A	p.Asn93Lys	missense	Exon 5 of 9	ENSP00000377947.2	P13631-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.18
Sift	Benign	0.058	T
Sift4G	Benign	0.78	T
Polyphen		0.99	D
Vest4		0.58
MutPred		0.38		Loss of stability (P = 0.0228)
MVP		0.46
MPC		1.7
ClinPred		0.99	D
GERP RS		2.1
Varity_R		0.57
gMVP		0.81
Mutation Taster		=8/92	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: rs745345035; hg19: chr12-53608371;