NM_207343.4:c.1227G>C

Variant names:

• chr11-117281395-G-C
• rs377379346
• NM_207343.4:c.1227G>C

Variant summary

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

The NM_207343.4(RNF214):​c.1227G>C​(p.Lys409Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RNF214 NM_207343.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.945
• Publications: 0 publications found

Genes affected

RNF214 (HGNC:25335): (ring finger protein 214) Predicted to enable ubiquitin-protein transferase activity. Predicted to be involved in protein ubiquitination. [provided by Alliance of Genome Resources, Apr 2022]

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=0.14034563).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207343.4. 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
	RNF214	NM_207343.4	MANE Select	c.1227G>C	p.Lys409Asn	missense	Exon 9 of 15	NP_997226.2	Q8ND24-1
	RNF214	NM_001077239.2		c.1227G>C	p.Lys409Asn	missense	Exon 9 of 15	NP_001070707.1	Q8ND24-1
	RNF214	NM_001278249.2		c.762G>C	p.Lys254Asn	missense	Exon 9 of 15	NP_001265178.1	Q8ND24-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF214	ENST00000300650.9	TSL:1 MANE Select	c.1227G>C	p.Lys409Asn	missense	Exon 9 of 15	ENSP00000300650.4	Q8ND24-1
	RNF214	ENST00000531452.5	TSL:1	c.1227G>C	p.Lys409Asn	missense	Exon 9 of 15	ENSP00000431643.1	Q8ND24-1
	RNF214	ENST00000852075.1		c.1227G>C	p.Lys409Asn	missense	Exon 9 of 15	ENSP00000522134.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458170 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725752

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

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

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108656

Other (OTH) AF: 0.00 AC: 0 AN: 60280

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.092
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.94
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.041
Sift	Uncertain	0.014	D
Sift4G	Benign	0.17	T
Polyphen		0.59	P
Vest4		0.18
MutPred		0.32		Gain of ubiquitination at K408 (P = 0.0982)
MVP		0.22
MPC		0.89
ClinPred		0.46	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.67
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs377379346; hg19: chr11-117152111;