12-53231170-C-G

Variant names:

• chr12-53231170-C-G
• rs7487904
• NM_000966.6:c.-144G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000966.6(RARG):​c.-144G>C variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 152,338 control chromosomes in the GnomAD database, including 6,370 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.23 (6367 hom., cov: 32)
  • Exomes 𝑓: 0.085 (3 hom.)
• Consequence: RARG NM_000966.6 splice_region
• Scores: Splicing: ADA: 0.00001209
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.155
• Publications: 9 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

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.-144G>C		splice_region	Exon 2 of 10	NP_000957.1	A8K3H3
	RARG	NM_000966.6	MANE Select	c.-144G>C		5_prime_UTR	Exon 2 of 10	NP_000957.1	A8K3H3
	RARG	NM_001243730.2		c.-34G>C		splice_region	Exon 2 of 9	NP_001230659.1	P13631-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARG	ENST00000425354.7	TSL:1 MANE Select	c.-144G>C		splice_region	Exon 2 of 10	ENSP00000388510.2	P13631-1
	RARG	ENST00000394426.5	TSL:1	c.-34G>C		splice_region	Exon 2 of 9	ENSP00000377947.2	P13631-3
	RARG	ENST00000425354.7	TSL:1 MANE Select	c.-144G>C		5_prime_UTR	Exon 2 of 10	ENSP00000388510.2	P13631-1

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35318 AN: 151936 Hom.: 6337 Cov.: 32

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.0973

Gnomad OTH AF: 0.185

GnomAD4 exome AF: 0.0851 AC: 24 AN: 282 Hom.: 3 Cov.: 0 AF XY: 0.0938 AC XY: 18 AN XY: 192

African (AFR) AF: 1.00 AC: 4 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.167 AC: 1 AN: 6

South Asian (SAS) AF: 0.500 AC: 1 AN: 2

European-Finnish (FIN) AF: 0.0455 AC: 2 AN: 44

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.0773 AC: 15 AN: 194

Other (OTH) AF: 0.0455 AC: 1 AN: 22

GnomAD4 genome AF: 0.233 AC: 35413 AN: 152056 Hom.: 6367 Cov.: 32 AF XY: 0.237 AC XY: 17589 AN XY: 74314

African (AFR) AF: 0.492 AC: 20399 AN: 41436

American (AMR) AF: 0.196 AC: 2993 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 349 AN: 3468

East Asian (EAS) AF: 0.231 AC: 1194 AN: 5180

South Asian (SAS) AF: 0.348 AC: 1675 AN: 4816

European-Finnish (FIN) AF: 0.150 AC: 1586 AN: 10574

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.0973 AC: 6614 AN: 67988

Other (OTH) AF: 0.187 AC: 395 AN: 2108

Alfa AF: 0.0999 Hom.: 584

Bravo AF: 0.241

Asia WGS AF: 0.337 AC: 1172 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.8
DANN	Benign	0.37
PhyloP100		0.15
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
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: rs7487904; hg19: chr12-53624954;