chr5-141978742-A-C

Variant names:

• chr5-141978742-A-C
• rs199953121
• NM_004290.5:c.746A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004290.5(RNF14):​c.746A>C​(p.Asp249Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000836 in 1,613,878 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 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000087 (0 hom.)
• Consequence: RNF14 NM_004290.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.27
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09109327).

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.746A>C	p.Asp249Ala	missense	Exon 5 of 9	NP_004281.1	Q9UBS8-1
	RNF14	NM_001201365.2		c.746A>C	p.Asp249Ala	missense	Exon 5 of 9	NP_001188294.1	Q9UBS8-1
	RNF14	NM_183399.3		c.746A>C	p.Asp249Ala	missense	Exon 4 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.746A>C	p.Asp249Ala	missense	Exon 5 of 9	ENSP00000378028.2	Q9UBS8-1
	RNF14	ENST00000356143.5	TSL:1	c.746A>C	p.Asp249Ala	missense	Exon 4 of 8	ENSP00000348462.1	Q9UBS8-1
	RNF14	ENST00000394519.5	TSL:1	c.746A>C	p.Asp249Ala	missense	Exon 5 of 9	ENSP00000378027.1	Q9UBS8-1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000139 AC: 35 AN: 251108 AF XY: 0.000133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000869 AC: 127 AN: 1461664 Hom.: 0 Cov.: 32 AF XY: 0.0000839 AC XY: 61 AN XY: 727142

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000447 AC: 2 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00360 AC: 94 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111836

Other (OTH) AF: 0.000149 AC: 9 AN: 60376

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000294 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000824 AC: 10

ClinVar

ClinVar submissions as Germline

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	0.20
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.091	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.091	T
MetaSVM	Uncertain	-0.037	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.024	D
Polyphen		0.073	B
Vest4		0.54
MVP		0.91
MPC		0.48
ClinPred		0.23	T
GERP RS		5.4
Varity_R		0.26
gMVP		0.57
Mutation Taster		=37/63	disease causing

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

Other links and lift over

dbSNP: rs199953121; hg19: chr5-141358307; COSMIC: COSV105260624; COSMIC: COSV105260624;