12-53211761-G-A

Position:

• chr12-53211761-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000966.6(RARG):​c.1280C>T​(p.Ser427Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0721 in 1,567,464 control chromosomes in the GnomAD database, including 5,112 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.073 (488 hom., cov: 32)
  • Exomes 𝑓: 0.072 (4624 hom.)
• Consequence: RARG NM_000966.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.49

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014831126).
• BP6: Variant 12-53211761-G-A is Benign according to our data. Variant chr12-53211761-G-A is described in ClinVar as [Benign]. Clinvar id is 1277170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RARG	NM_000966.6	c.1280C>T	p.Ser427Leu	missense_variant	10/10	ENST00000425354.7	NP_000957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RARG	ENST00000425354.7	c.1280C>T	p.Ser427Leu	missense_variant	10/10	1	NM_000966.6	ENSP00000388510	A2

Frequencies

GnomAD3 genomes AF: 0.0731 AC: 11124 AN: 152106 Hom.: 484 Cov.: 32

Gnomad AFR AF: 0.0851

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0582

Gnomad ASJ AF: 0.0588

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.0523

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0703

Gnomad OTH AF: 0.0712

GnomAD3 exomes AF: 0.0734 AC: 15716 AN: 214176 Hom.: 877 AF XY: 0.0793 AC XY: 9282 AN XY: 117104

Gnomad AFR exome AF: 0.0840

Gnomad AMR exome AF: 0.0309

Gnomad ASJ exome AF: 0.0576

Gnomad EAS exome AF: 0.00253

Gnomad SAS exome AF: 0.186

Gnomad FIN exome AF: 0.0546

Gnomad NFE exome AF: 0.0694

Gnomad OTH exome AF: 0.0745

GnomAD4 exome AF: 0.0720 AC: 101891 AN: 1415240 Hom.: 4624 Cov.: 31 AF XY: 0.0749 AC XY: 52520 AN XY: 701460

Gnomad4 AFR exome AF: 0.0799

Gnomad4 AMR exome AF: 0.0346

Gnomad4 ASJ exome AF: 0.0575

Gnomad4 EAS exome AF: 0.00151

Gnomad4 SAS exome AF: 0.177

Gnomad4 FIN exome AF: 0.0557

Gnomad4 NFE exome AF: 0.0682

Gnomad4 OTH exome AF: 0.0776

GnomAD4 genome AF: 0.0732 AC: 11137 AN: 152224 Hom.: 488 Cov.: 32 AF XY: 0.0734 AC XY: 5463 AN XY: 74432

Gnomad4 AFR AF: 0.0849

Gnomad4 AMR AF: 0.0582

Gnomad4 ASJ AF: 0.0588

Gnomad4 EAS AF: 0.00367

Gnomad4 SAS AF: 0.185

Gnomad4 FIN AF: 0.0523

Gnomad4 NFE AF: 0.0703

Gnomad4 OTH AF: 0.0766

Alfa AF: 0.0694 Hom.: 982

Bravo AF: 0.0695

TwinsUK AF: 0.0677 AC: 251

ALSPAC AF: 0.0685 AC: 264

ESP6500AA AF: 0.0887 AC: 391

ESP6500EA AF: 0.0649 AC: 558

ExAC AF: 0.0794 AC: 9640

Asia WGS AF: 0.154 AC: 538 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2019	This variant is associated with the following publications: (PMID: 26237429) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	.;T;.;.
Eigen	Benign	-0.035
Eigen_PC	Benign	0.032
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.93	D;D;D;D
MetaRNN	Benign	0.0015	T;T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.4	.;L;.;.
MutationTaster	Benign	0.095	P;P;P;P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	.;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.047	.;D;D;D
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.22	.;B;.;.
Vest4		0.11
MPC		0.44
ClinPred		0.0061	T
GERP RS		4.5
Varity_R		0.088
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs2229774; hg19: chr12-53605545;