Genetic Variant RNF14:p.Met303Leu (chr5-141980195-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004290.5(RNF14):c.907A>T(p.Met303Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RNF14
NM_004290.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.41

Variant links:

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]

RNF14 links:

ENSG00000254099 (HGNC:):

ENSG00000254099 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF14	NM_004290.5 link	c.907A>T	p.Met303Leu	missense_variant	Exon 6 of 9	ENST00000394520.7	NP_004281.1	Q9UBS8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF14	ENST00000394520.7 link	c.907A>T	p.Met303Leu	missense_variant	Exon 6 of 9	1	NM_004290.5	ENSP00000378028.2		Q9UBS8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.907A>T (p.M303L) alteration is located in exon 6 (coding exon 4) of the RNF14 gene. This alteration results from a A to T substitution at nucleotide position 907, causing the methionine (M) at amino acid position 303 to be replaced by a leucine (L). 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

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.62

D;D;D;D;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

.;.;D;.;D

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.61

D;D;D;D;D

MetaSVM

Uncertain

0.21

MutationAssessor

Pathogenic

3.0

M;M;M;M;.

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-2.7

D;D;D;D;D

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Benign

0.063

T;T;T;T;T

Polyphen

0.99

D;D;D;D;.

Vest4

0.55

MutPred

0.62

Gain of catalytic residue at M303 (P = 0.0373);Gain of catalytic residue at M303 (P = 0.0373);Gain of catalytic residue at M303 (P = 0.0373);Gain of catalytic residue at M303 (P = 0.0373);.;

MVP

0.76

MPC

1.1

ClinPred

0.97

GERP RS

5.0

Varity_R

0.77

gMVP

0.62

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over