5-141980349-C-T

Variant names:

• chr5-141980349-C-T
• NM_004290.5:c.1061C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004290.5(RNF14):​c.1061C>T​(p.Ala354Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RNF14 NM_004290.5 missense, splice_region
• Scores: Splicing: ADA: 0.9906
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.81
• Publications: 0 publications found

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]

ENSG00000254099 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004290.5. 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
	RNF14	NM_004290.5	MANE Select	c.1061C>T	p.Ala354Val	missense splice_region	Exon 6 of 9	NP_004281.1	Q9UBS8-1
	RNF14	NM_001201365.2		c.1061C>T	p.Ala354Val	missense splice_region	Exon 6 of 9	NP_001188294.1	Q9UBS8-1
	RNF14	NM_183399.3		c.1061C>T	p.Ala354Val	missense splice_region	Exon 5 of 8	NP_899646.1	Q9UBS8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF14	ENST00000394520.7	TSL:1 MANE Select	c.1061C>T	p.Ala354Val	missense splice_region	Exon 6 of 9	ENSP00000378028.2	Q9UBS8-1
	RNF14	ENST00000356143.5	TSL:1	c.1061C>T	p.Ala354Val	missense splice_region	Exon 5 of 8	ENSP00000348462.1	Q9UBS8-1
	RNF14	ENST00000394519.5	TSL:1	c.1061C>T	p.Ala354Val	missense splice_region	Exon 6 of 9	ENSP00000378027.1	Q9UBS8-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.15
Sift	Benign	0.081	T
Sift4G	Benign	0.22	T
Polyphen		0.67	P
Vest4		0.46
MutPred		0.45		Gain of loop (P = 0.0079)
MVP		0.79
MPC		0.53
ClinPred		0.91	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.27
gMVP		0.58
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr5-141359914;