5-141974829-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004290.5(RNF14):c.180T>G(p.Asn60Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: RNF14 NM_004290.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15

Genes affected

RNF14 (HGNC:10058): (ring finger protein 14) The protein encoded by this gene contains a RING zinc finger, a motif known to be involved in protein-protein interactions. This protein interacts with androgen receptor (AR) and may function as a coactivator that induces AR target gene expression in prostate. A dominant negative mutant of this gene has been demonstrated to inhibit the AR-mediated growth of prostate cancer. This protein also interacts with class III ubiquitin-conjugating enzymes (E2s) and may act as a ubiquitin-ligase (E3) in the ubiquitination of certain nuclear proteins. Six alternatively spliced transcript variants encoding two distinct isoforms have been reported. [provided by RefSeq, Jan 2011]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.035763204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF14	NM_004290.5	c.180T>G	p.Asn60Lys	missense_variant	4/9	ENST00000394520.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF14	ENST00000394520.7	c.180T>G	p.Asn60Lys	missense_variant	4/9	1	NM_004290.5	P1
	ENST00000520882.1	n.157-4005A>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000271 AC: 68 AN: 251334 Hom.: 0 AF XY: 0.000265 AC XY: 36 AN XY: 135842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000191 AC: 279 AN: 1461712 Hom.: 0 Cov.: 31 AF XY: 0.000180 AC XY: 131 AN XY: 727152

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000209

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000320 Hom.: 0

Bravo AF: 0.000170

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000491

EpiControl AF: 0.000119

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

Mar 03, 2022

The c.180T>G (p.N60K) alteration is located in exon 4 (coding exon 2) of the RNF14 gene. This alteration results from a T to G substitution at nucleotide position 180, causing the asparagine (N) at amino acid position 60 to be replaced by a lysine (K). 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	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	20
Dann	Benign	0.92
DEOGEN2	Benign	0.030	T;.;T;T;T;T;T;.;.;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.70	T;T;T;.;.;T;.;T;T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.036	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;N;N;N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.56	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.063
Sift	Benign	0.29	T;T;T;T;T;T;T;T;T;D
Sift4G	Benign	0.87	T;T;T;T;T;T;T;T;T;D
Polyphen		0.018	.;.;.;B;B;B;B;.;.;.
Vest4		0.16, 0.14, 0.14, 0.14
MutPred		0.51		Gain of ubiquitination at N60 (P = 0.0104);Gain of ubiquitination at N60 (P = 0.0104);Gain of ubiquitination at N60 (P = 0.0104);Gain of ubiquitination at N60 (P = 0.0104);Gain of ubiquitination at N60 (P = 0.0104);Gain of ubiquitination at N60 (P = 0.0104);Gain of ubiquitination at N60 (P = 0.0104);Gain of ubiquitination at N60 (P = 0.0104);Gain of ubiquitination at N60 (P = 0.0104);Gain of ubiquitination at N60 (P = 0.0104);
MVP		0.52
MPC		0.44
ClinPred		0.019	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.065
gMVP		0.25

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: rs367880202; hg19: chr5-141354394;