3-158732196-A-G

Position:

• chr3-158732196-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_206963.2(RARRES1):​c.220T>C​(p.Ser74Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000709 in 1,270,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: RARRES1 NM_206963.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0390

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]

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15075901).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RARRES1	NM_206963.2	c.220T>C	p.Ser74Pro	missense_variant	1/6	ENST00000237696.10	NP_996846.1
RARRES1	NM_002888.4	c.220T>C	p.Ser74Pro	missense_variant	1/4		NP_002879.2
RARRES1	XM_005247686.6	c.220T>C	p.Ser74Pro	missense_variant	1/6		XP_005247743.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RARRES1	ENST00000237696.10	c.220T>C	p.Ser74Pro	missense_variant	1/6	1	NM_206963.2	ENSP00000237696	P1
RARRES1	ENST00000479756.1	c.220T>C	p.Ser74Pro	missense_variant	1/4	1		ENSP00000418556
RARRES1	ENST00000498640.1	n.294T>C		non_coding_transcript_exon_variant	1/3	3
MFSD1	ENST00000486568.5			upstream_gene_variant		4		ENSP00000417414

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000709 AC: 9 AN: 1270146 Hom.: 0 Cov.: 38 AF XY: 0.00000481 AC XY: 3 AN XY: 624110

Gnomad4 AFR exome AF: 0.0000395

Gnomad4 AMR exome AF: 0.000211

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000390

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

The c.220T>C (p.S74P) alteration is located in exon 1 (coding exon 1) of the RARRES1 gene. This alteration results from a T to C substitution at nucleotide position 220, causing the serine (S) at amino acid position 74 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.0035	T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.28	T;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.60	N;N
REVEL	Benign	0.084
Sift	Benign	0.25	T;T
Sift4G	Uncertain	0.016	D;D
Polyphen		0.96	D;P
Vest4		0.22
MutPred		0.48		Loss of MoRF binding (P = 0.0517);Loss of MoRF binding (P = 0.0517);
MVP		0.34
MPC		1.1
ClinPred		0.16	T
GERP RS		0.86
Varity_R		0.11
gMVP		0.35

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: rs1421444552; hg19: chr3-158449985;