17-58370936-C-T

Variant names:

• chr17-58370936-C-T
• rs2257205
• NM_017763.6:c.350G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017763.6(RNF43):​c.350G>A​(p.Arg117His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,605,284 control chromosomes in the GnomAD database, including 16,938 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R117C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.15 (1963 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14975 hom.)
• Consequence: RNF43 NM_017763.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.00
• Publications: 66 publications found

Genes affected

RNF43 (HGNC:18505): (ring finger protein 43) The protein encoded by this gene is a RING-type E3 ubiquitin ligase and is predicted to contain a transmembrane domain, a protease-associated domain, an ectodomain, and a cytoplasmic RING domain. This protein is thought to negatively regulate Wnt signaling, and expression of this gene results in an increase in ubiquitination of frizzled receptors, an alteration in their subcellular distribution, resulting in reduced surface levels of these receptors. Mutations in this gene have been reported in multiple tumor cells, including colorectal and endometrial cancers. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2015]

ENSG00000285897 (HGNC:):

TSPOAP1-AS1 (HGNC:44148): (TSPOAP1, SUPT4H1 and RNF43 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032409728).
• BP6: Variant 17-58370936-C-T is Benign according to our data. Variant chr17-58370936-C-T is described in ClinVar as Benign. ClinVar VariationId is 1165517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017763.6. 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
	RNF43	NM_017763.6	MANE Select	c.350G>A	p.Arg117His	missense	Exon 3 of 10	NP_060233.3
	RNF43	NM_001438820.1		c.350G>A	p.Arg117His	missense	Exon 4 of 10	NP_001425749.1
	RNF43	NM_001438821.1		c.350G>A	p.Arg117His	missense	Exon 3 of 9	NP_001425750.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF43	ENST00000407977.7	TSL:2 MANE Select	c.350G>A	p.Arg117His	missense	Exon 3 of 10	ENSP00000385328.2	Q68DV7-1
	RNF43	ENST00000577716.5	TSL:1	c.350G>A	p.Arg117His	missense	Exon 3 of 10	ENSP00000462764.1	Q68DV7-1
	RNF43	ENST00000584437.5	TSL:1	c.350G>A	p.Arg117His	missense	Exon 2 of 9	ENSP00000463069.1	Q68DV7-1

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22491 AN: 151854 Hom.: 1958 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.0981

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.128

GnomAD2 exomes AF: 0.158 AC: 38482 AN: 243942 AF XY: 0.164

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.0710

Gnomad ASJ exome AF: 0.165

Gnomad EAS exome AF: 0.386

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.128 AC: 185550 AN: 1453312 Hom.: 14975 Cov.: 31 AF XY: 0.132 AC XY: 95544 AN XY: 722512

African (AFR) AF: 0.187 AC: 6227 AN: 33354

American (AMR) AF: 0.0743 AC: 3272 AN: 44020

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 4248 AN: 25614

East Asian (EAS) AF: 0.354 AC: 14029 AN: 39594

South Asian (SAS) AF: 0.290 AC: 24585 AN: 84690

European-Finnish (FIN) AF: 0.146 AC: 7746 AN: 53074

Middle Eastern (MID) AF: 0.131 AC: 750 AN: 5712

European-Non Finnish (NFE) AF: 0.105 AC: 116082 AN: 1107230

Other (OTH) AF: 0.143 AC: 8611 AN: 60024

GnomAD4 genome AF: 0.148 AC: 22517 AN: 151972 Hom.: 1963 Cov.: 32 AF XY: 0.154 AC XY: 11419 AN XY: 74256

African (AFR) AF: 0.186 AC: 7694 AN: 41442

American (AMR) AF: 0.0982 AC: 1500 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 541 AN: 3464

East Asian (EAS) AF: 0.374 AC: 1923 AN: 5146

South Asian (SAS) AF: 0.312 AC: 1499 AN: 4798

European-Finnish (FIN) AF: 0.148 AC: 1568 AN: 10566

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7357 AN: 67966

Other (OTH) AF: 0.132 AC: 279 AN: 2110

Alfa AF: 0.122 Hom.: 6173

Bravo AF: 0.143

TwinsUK AF: 0.110 AC: 408

ALSPAC AF: 0.107 AC: 414

ESP6500AA AF: 0.185 AC: 816

ESP6500EA AF: 0.109 AC: 936

ExAC AF: 0.160 AC: 19385

Asia WGS AF: 0.341 AC: 1186 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	RNF43-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.14
MPC		0.53
ClinPred		0.019	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.73
Mutation Taster		=295/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2257205; hg19: chr17-56448297; COSMIC: COSV68457011;