rs2526374

Variant names:

• chr17-58358524-G-T
• rs2526374
• NM_017763.6:c.1252C>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.1252C>A​(p.Leu418Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 1,612,932 control chromosomes in the GnomAD database, including 112,612 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L418I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.38 (10990 hom., cov: 33)
  • Exomes 𝑓: 0.37 (101622 hom.)
• Consequence: RNF43 NM_017763.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.49
• Publications: 41 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=1.885891E-4).
• BP6: Variant 17-58358524-G-T is Benign according to our data. Variant chr17-58358524-G-T is described in ClinVar as Benign. ClinVar VariationId is 403384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.435 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.1252C>A	p.Leu418Met	missense	Exon 9 of 10	NP_060233.3
	RNF43	NM_001438820.1		c.1252C>A	p.Leu418Met	missense	Exon 10 of 10	NP_001425749.1
	RNF43	NM_001438821.1		c.1252C>A	p.Leu418Met	missense	Exon 9 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.1252C>A	p.Leu418Met	missense	Exon 9 of 10	ENSP00000385328.2	Q68DV7-1
	RNF43	ENST00000577716.5	TSL:1	c.1252C>A	p.Leu418Met	missense	Exon 9 of 10	ENSP00000462764.1	Q68DV7-1
	RNF43	ENST00000584437.5	TSL:1	c.1252C>A	p.Leu418Met	missense	Exon 8 of 9	ENSP00000463069.1	Q68DV7-1

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57445 AN: 151970 Hom.: 10974 Cov.: 33

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.437

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.375

GnomAD2 exomes AF: 0.395 AC: 98463 AN: 249256 AF XY: 0.387

Gnomad AFR exome AF: 0.405

Gnomad AMR exome AF: 0.561

Gnomad ASJ exome AF: 0.336

Gnomad EAS exome AF: 0.460

Gnomad FIN exome AF: 0.317

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.384

GnomAD4 exome AF: 0.370 AC: 540390 AN: 1460844 Hom.: 101622 Cov.: 52 AF XY: 0.368 AC XY: 267707 AN XY: 726646

African (AFR) AF: 0.414 AC: 13873 AN: 33478

American (AMR) AF: 0.542 AC: 24161 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.336 AC: 8768 AN: 26088

East Asian (EAS) AF: 0.447 AC: 17740 AN: 39680

South Asian (SAS) AF: 0.360 AC: 30984 AN: 86144

European-Finnish (FIN) AF: 0.321 AC: 17087 AN: 53204

Middle Eastern (MID) AF: 0.365 AC: 2102 AN: 5764

European-Non Finnish (NFE) AF: 0.363 AC: 403259 AN: 1111580

Other (OTH) AF: 0.371 AC: 22416 AN: 60344

GnomAD4 genome AF: 0.378 AC: 57488 AN: 152088 Hom.: 10990 Cov.: 33 AF XY: 0.377 AC XY: 28006 AN XY: 74354

African (AFR) AF: 0.400 AC: 16571 AN: 41468

American (AMR) AF: 0.437 AC: 6683 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1157 AN: 3464

East Asian (EAS) AF: 0.451 AC: 2330 AN: 5172

South Asian (SAS) AF: 0.366 AC: 1770 AN: 4832

European-Finnish (FIN) AF: 0.319 AC: 3378 AN: 10580

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.359 AC: 24385 AN: 67966

Other (OTH) AF: 0.376 AC: 793 AN: 2110

Alfa AF: 0.371 Hom.: 46261

Bravo AF: 0.391

TwinsUK AF: 0.358 AC: 1329

ALSPAC AF: 0.359 AC: 1383

ESP6500AA AF: 0.402 AC: 1773

ESP6500EA AF: 0.359 AC: 3088

ExAC AF: 0.389 AC: 47235

Asia WGS AF: 0.397 AC: 1378 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.00019	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.11
Sift	Benign	0.064	T
Sift4G	Uncertain	0.050	T
Polyphen		0.95	P
Vest4		0.071
MPC		0.41
ClinPred		0.015	T
GERP RS		4.2
Varity_R		0.11
gMVP		0.11
Mutation Taster		=99/1	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: rs2526374; hg19: chr17-56435885; COSMIC: COSV68456749; COSMIC: COSV68456749;