3-158732382-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_206963.2(RARRES1):c.34T>C(p.Trp12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000022 in 1,501,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: RARRES1 NM_206963.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.01

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]

(HGNC:):

MFSD1 (HGNC:25874): (major facilitator superfamily domain containing 1) Predicted to enable protein homodimerization activity. Predicted to be involved in protein localization to lysosome and protein stabilization. Predicted to be located in lysosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02784124).
• BP6: Variant 3-158732382-A-G is Benign according to our data. Variant chr3-158732382-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3151658.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RARRES1	NM_206963.2	c.34T>C	p.Trp12Arg	missense_variant	1/6	ENST00000237696.10
LOC100287290	NR_171782.1	n.22A>G		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RARRES1	ENST00000237696.10	c.34T>C	p.Trp12Arg	missense_variant	1/6	1	NM_206963.2	P1
	ENST00000465477.5	n.56A>G		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 151950 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000202 AC: 2 AN: 98962 Hom.: 0 AF XY: 0.0000180 AC XY: 1 AN XY: 55438

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000475

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: 0.0000284

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 24 AN: 1349460 Hom.: 0 Cov.: 41 AF XY: 0.0000195 AC XY: 13 AN XY: 665476

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000304

Gnomad4 ASJ exome AF: 0.0000419

Gnomad4 EAS exome AF: 0.0000318

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000188

Gnomad4 OTH exome AF: 0.0000178

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 151950 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74240

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000604

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	2.7
Dann	Benign	0.46
DEOGEN2	Benign	0.00097	T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.18	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.028	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.030	N;N
REVEL	Benign	0.030
Sift	Benign	0.88	T;T
Sift4G	Benign	0.82	T;T
Polyphen		0.0	B;B
Vest4		0.047
MutPred		0.23		Gain of methylation at W12 (P = 0.0118);Gain of methylation at W12 (P = 0.0118);
MVP		0.13
MPC		0.90
ClinPred		0.024	T
GERP RS		-2.9
Varity_R		0.052
gMVP		0.16

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: rs754539084; hg19: chr3-158450171;