chr14-24147702-C-T

Position:

• chr14-24147702-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017999.5(RNF31):​c.4C>T​(p.Pro2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000295 in 1,357,720 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: RNF31 NM_017999.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.906

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26991934).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF31	NM_017999.5	c.4C>T	p.Pro2Ser	missense_variant	1/21	ENST00000324103.11
RNF31	NM_001310332.2	c.-325-274C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF31	ENST00000324103.11	c.4C>T	p.Pro2Ser	missense_variant	1/21	1	NM_017999.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000295 AC: 4 AN: 1357720 Hom.: 0 Cov.: 31 AF XY: 0.00000299 AC XY: 2 AN XY: 669042

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000115

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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 provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 29, 2022

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2 of the RNF31 protein (p.Pro2Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RNF31-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	0.090
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	.;.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.36	N
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	.;.;N
MutationTaster	Benign	0.82	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.3	D;N;N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;T;T
Polyphen		0.015	.;.;B
Vest4		0.18
MutPred		0.32		Gain of phosphorylation at P2 (P = 0.0023);Gain of phosphorylation at P2 (P = 0.0023);Gain of phosphorylation at P2 (P = 0.0023);
MVP		0.56
MPC		0.85
ClinPred		0.67	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.31

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: rs1425454934; hg19: chr14-24616911;