11-117281395-G-T

Variant names:

• chr11-117281395-G-T
• rs377379346
• NM_207343.4:c.1227G>T
• RNF214 p.Lys409Asn

Variant summary

Our verdict is Likely benign.

-1 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -1 classification points (ACGS-UK Somatic Oncogenicity v2025). B3_Supporting

The NM_207343.4(RNF214):c.1227G>T (p.Lys409Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene RNF214 is a known oncogene (CancerMine: 2 oncogene citations). The variant allele was found at a cumulative frequency of 0.0000391 (AC=63) in the gnomAD database across 1,610,292 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000299. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: RNF214 NM_207343.4 missense
• Predictors: REVEL: 0.042: Benign
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.945
• Publications: 0 publications found

Genes affected

RNF214 (HGNC:25335): (ring finger protein 214) Predicted to enable ubiquitin-protein transferase activity. [provided by Alliance of Genome Resources, Jul 2025]

BACE1 (HGNC:933): (beta-secretase 1) This gene encodes a member of the peptidase A1 family of aspartic proteases. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature protease. This transmembrane protease catalyzes the first step in the formation of amyloid beta peptide from amyloid precursor protein. Amyloid beta peptides are the main constituent of amyloid beta plaques, which accumulate in the brains of human Alzheimer's disease patients. [provided by RefSeq, Nov 2015]

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_207343.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RNF214 NM_207343.4	MANE Select	c.1227G>T p.Lys409Asn	missense	Exon 9 of 15	Prot: NP_997226.2
	RNF214 NM_001077239.2		c.1227G>T p.Lys409Asn	missense	Exon 9 of 15	Prot: NP_001070707.1
	RNF214 NM_001278249.2		c.762G>T p.Lys254Asn	missense	Exon 9 of 15	Prot: NP_001265178.1

RNF214 NM_207343.4

MANE Select

HGVSc / HGVSpc.1227G>Tp.Lys409Asn

Exon rankExon 9 of 15

missense

Prot: NP_997226.2

RNF214 NM_001077239.2

HGVSc / HGVSpc.1227G>Tp.Lys409Asn

Exon rankExon 9 of 15

missense

Prot: NP_001070707.1

RNF214 NM_001278249.2

HGVSc / HGVSpc.762G>Tp.Lys254Asn

Exon rankExon 9 of 15

missense

Prot: NP_001265178.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RNF214 ENST00000300650.9	MANE Select	c.1227G>T p.Lys409Asn	missense	Exon 9 of 15	Prot: ENSP00000300650
	RNF214 ENST00000531452.6	TSL:1	c.1227G>T p.Lys409Asn	missense	Exon 9 of 15	Prot: ENSP00000431643
	RNF214 ENST00000852075.2		c.1227G>T p.Lys409Asn	missense	Exon 9 of 15	Prot: ENSP00000522134

RNF214 ENST00000300650.9

MANE Select

HGVSc / HGVSpc.1227G>Tp.Lys409Asn

Exon rankExon 9 of 15

missense

Prot: ENSP00000300650

RNF214 ENST00000531452.6

TSL:1

HGVSc / HGVSpc.1227G>Tp.Lys409Asn

Exon rankExon 9 of 15

missense

Prot: ENSP00000431643

RNF214 ENST00000852075.2

HGVSc / HGVSpc.1227G>Tp.Lys409Asn

Exon rankExon 9 of 15

missense

Prot: ENSP00000522134

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000145	AC:22	Hom:0	AN:152004	Cov:30
GnomAD2 exomes	AF: 0.0000962	AC:24	Hom:	AN:249464	Cov:
GnomAD4 exome	AF: 0.0000281	AC:41	Hom:0	AN:1458170	Cov:29
GnomAD4 genome	AF: 0.000145	AC:22	Hom:0	AN:152122	Cov:30
TOPMed (Bravo)	AF: 0.000113	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000358	AC:19	Hom:0	AN:53146	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.000345	AC:	Hom:	AN:	Cov:
GenomeAsia100K	AF: 0.00260	AC:9	Hom:	AN:3478	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000558	AC:5	Hom:0	AN:8960	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000238	1	41958	0.0000150	1	66834
SCHEMA(Schizophrenia)	0.000212	24	113070	0.0000840	16	190468

Showing 2 cohortsAllele count / allele number. *AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.092
FATHMM_MKL	Benign	0.59	D
FuncVEP CTI	Benign	0.0013
GPN-Star LLR	N/A	-6.5
GPN-Star score	N/A	6.5
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.69	T
Mutation Taster	N/A	85/15	polymorphism
MutationAssessor	Benign	0.34	N
PhyloP100	Benign	0.94
popEVE	Benign	-2.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.92	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Benign	0.042
Sift	Uncertain	0.014	D
Sift4G	Benign	0.17	T
Varity_R	N/A	0.11
VESM-3B	Benign	-8.2

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.080
SpliceAI score (max)	Benign	0.080	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs377379346;

hg19: chr11-117152111;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar