NM_206963.2:c.277A>C

Variant names:

• chr3-158713859-T-G
• rs201288879
• NM_206963.2:c.277A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_206963.2(RARRES1):​c.277A>C​(p.Ile93Leu) variant causes a missense, splice region 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. 18/24 in silico tools predict 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I93V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RARRES1 NM_206963.2 missense, splice_region
• Scores: Splicing: ADA: 0.0008211
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.329
• Publications: 0 publications found

Genes affected

RARRES1 (HGNC:9867): (retinoic acid receptor responder 1) This gene was identified as a retinoid acid (RA) receptor-responsive gene. It encodes a type 1 membrane protein. The expression of this gene is upregulated by tazarotene as well as by retinoic acid receptors. The expression of this gene is found to be downregulated in prostate cancer, which is caused by the methylation of its promoter and CpG island. Alternatively spliced transcript variant encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.006422758).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206963.2. 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
	RARRES1	NM_206963.2	MANE Select	c.277A>C	p.Ile93Leu	missense splice_region	Exon 2 of 6	NP_996846.1	P49788-1
	RARRES1	NM_002888.4		c.277A>C	p.Ile93Leu	missense splice_region	Exon 2 of 4	NP_002879.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARRES1	ENST00000237696.10	TSL:1 MANE Select	c.277A>C	p.Ile93Leu	missense splice_region	Exon 2 of 6	ENSP00000237696.5	P49788-1
	RARRES1	ENST00000479756.1	TSL:1	c.277A>C	p.Ile93Leu	missense splice_region	Exon 2 of 4	ENSP00000418556.1	P49788-2
	RARRES1	ENST00000879325.1		c.277A>C	p.Ile93Leu	missense splice_region	Exon 2 of 6	ENSP00000549384.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00323 AC: 810 AN: 250418 AF XY: 0.00202

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00488

Gnomad OTH exome AF: 0.00311

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000131 AC: 191 AN: 1460856 Hom.: 0 Cov.: 30 AF XY: 0.000168 AC XY: 122 AN XY: 726838

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000134 AC: 149 AN: 1111118

Other (OTH) AF: 0.000315 AC: 19 AN: 60352

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ExAC AF: 0.00567 AC: 688

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	13
DANN	Benign	0.65
DEOGEN2	Benign	0.0054	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M
PhyloP100		-0.33
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.052
Sift	Benign	0.35	T
Sift4G	Benign	0.062	T
Polyphen		0.017	B
Vest4		0.29
MVP		0.12
MPC		0.45
ClinPred		0.0041	T
GERP RS		-1.9
Varity_R		0.061
gMVP		0.18
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00082
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.11		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: rs201288879; hg19: chr3-158431648; COSMIC: COSV52962190; COSMIC: COSV52962190;