rs981634882

Variant names:

• chr14-24147757-C-T
• rs981634882
• NM_017999.5:c.59C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_017999.5(RNF31):​c.59C>T​(p.Ala20Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000147 in 1,569,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: RNF31 NM_017999.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34

Genes affected

RNF31 (HGNC:16031): (ring finger protein 31) The protein encoded by this gene contains a RING finger, a motif present in a variety of functionally distinct proteins and known to be involved in protein-DNA and protein-protein interactions. The encoded protein is the E3 ubiquitin-protein ligase component of the linear ubiquitin chain assembly complex. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

ENSG00000259529 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21610588).
• BS2: High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF31	NM_017999.5	c.59C>T	p.Ala20Val	missense_variant	Exon 1 of 21	ENST00000324103.11	NP_060469.4
RNF31	NM_001310332.2	c.-325-219C>T		intron_variant	Intron 1 of 20		NP_001297261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF31	ENST00000324103.11	c.59C>T	p.Ala20Val	missense_variant	Exon 1 of 21	1	NM_017999.5	ENSP00000315112.6
ENSG00000259529	ENST00000558468.2	n.59C>T		non_coding_transcript_exon_variant	Exon 1 of 29	2		ENSP00000457512.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000155 AC: 22 AN: 1417662 Hom.: 0 Cov.: 31 AF XY: 0.0000142 AC XY: 10 AN XY: 702016

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000201

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 20 of the RNF31 protein (p.Ala20Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RNF31-related conditions. ClinVar contains an entry for this variant (Variation ID: 2900829). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	.;.;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;.;L
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.0	D;N;N
REVEL	Benign	0.078
Sift	Uncertain	0.0060	D;D;T
Sift4G	Pathogenic	0.0	D;T;T
Polyphen		0.44	.;.;B
Vest4		0.33
MutPred		0.27		Gain of catalytic residue at D24 (P = 0.0676);Gain of catalytic residue at D24 (P = 0.0676);Gain of catalytic residue at D24 (P = 0.0676);
MVP		0.39
MPC		0.39
ClinPred		0.96	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.30

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: rs981634882; hg19: chr14-24616966;