NM_000966.6:c.29C>A

Variant names:

• chr12-53227517-G-T
• rs369873803
• NM_000966.6:c.29C>A

Variant summary

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

The NM_000966.6(RARG):​c.29C>A​(p.Ala10Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RARG NM_000966.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.394

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

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=0.14210683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARG	NM_000966.6	c.29C>A	p.Ala10Glu	missense_variant	Exon 3 of 10	ENST00000425354.7	NP_000957.1
RARG	NM_001243730.2	c.-33+3652C>A		intron_variant	Intron 2 of 8		NP_001230659.1
RARG	NM_001243731.2	c.-31+3652C>A		intron_variant	Intron 2 of 7		NP_001230660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARG	ENST00000425354.7	c.29C>A	p.Ala10Glu	missense_variant	Exon 3 of 10	1	NM_000966.6	ENSP00000388510.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000434 AC: 1 AN: 230414 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 125670

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000326

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445094 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718646

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000238

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.16	T;T;.;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.64	T;T;T;.
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.0	N;.;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.59	N;D;D;D
REVEL	Benign	0.24
Sift	Benign	0.14	T;.;.;.
Sift4G	Benign	0.28	T;.;.;.
Polyphen		0.39	B;.;.;.
Vest4		0.27
MutPred		0.40		Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);
MVP		0.78
MPC		1.7
ClinPred		0.19	T
GERP RS		1.2
Varity_R		0.045
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs369873803; hg19: chr12-53621301;