chr3-158732382-A-T

Position:

• chr3-158732382-A-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000237696.10(RARRES1):​c.34T>A​(p.Trp12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0036 in 1,501,498 control chromosomes in the GnomAD database, including 18 homozygotes. 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 0.0027 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (16 hom.)
• Consequence: RARRES1 ENST00000237696.10 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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005034983).
• BP6: Variant 3-158732382-A-T is Benign according to our data. Variant chr3-158732382-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 2344505.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RARRES1	NM_206963.2	c.34T>A	p.Trp12Arg	missense_variant	1/6	ENST00000237696.10	NP_996846.1
LOC100287290	NR_171782.1	n.22A>T		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RARRES1	ENST00000237696.10	c.34T>A	p.Trp12Arg	missense_variant	1/6	1	NM_206963.2	ENSP00000237696	P1
	ENST00000465477.5	n.56A>T		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 408 AN: 151950 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00199

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00452

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00186 AC: 184 AN: 98962 Hom.: 0 AF XY: 0.00204 AC XY: 113 AN XY: 55438

Gnomad AFR exome AF: 0.000631

Gnomad AMR exome AF: 0.000855

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000355

Gnomad FIN exome AF: 0.00138

Gnomad NFE exome AF: 0.00352

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00371 AC: 5003 AN: 1349438 Hom.: 16 Cov.: 41 AF XY: 0.00364 AC XY: 2421 AN XY: 665468

Gnomad4 AFR exome AF: 0.000511

Gnomad4 AMR exome AF: 0.000913

Gnomad4 ASJ exome AF: 0.00164

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000445

Gnomad4 FIN exome AF: 0.00211

Gnomad4 NFE exome AF: 0.00434

Gnomad4 OTH exome AF: 0.00352

GnomAD4 genome AF: 0.00268 AC: 408 AN: 152060 Hom.: 2 Cov.: 33 AF XY: 0.00250 AC XY: 186 AN XY: 74358

Gnomad4 AFR AF: 0.000795

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00199

Gnomad4 NFE AF: 0.00452

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00119 Hom.: 0

Bravo AF: 0.00262

ExAC AF: 0.000290 AC: 5

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

Sep 01, 2021

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	-0.70	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.3
DANN	Benign	0.50
DEOGEN2	Benign	0.00097	T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.18	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0050	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	0.031
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		0.0023	T
GERP RS		-2.9
Varity_R		0.052
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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;