chr11-117281395-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_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 has a gnomAD grpmax filtering allele frequency (95% CI) of 0.000000902, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.K409N: Uncertain_significance (ClinVar VariationId 3155290, 1 star)

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0 (0 hom.)
• Consequence: RNF214 NM_207343.4 missense
• Predictors: REVEL: 0.041: Benign
• 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. [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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000902 — very rare for unknown gene (threshold 0.001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

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>C p.Lys409Asn	missense	Exon 9 of 15	Prot: NP_997226.2
	RNF214 NM_001077239.2		c.1227G>C p.Lys409Asn	missense	Exon 9 of 15	Prot: NP_001070707.1
	RNF214 NM_001278249.2		c.762G>C p.Lys254Asn	missense	Exon 9 of 15	Prot: NP_001265178.1

RNF214 NM_207343.4

MANE Select

HGVSc / HGVSpc.1227G>Cp.Lys409Asn

Exon rankExon 9 of 15

missense

Prot: NP_997226.2

RNF214 NM_001077239.2

HGVSc / HGVSpc.1227G>Cp.Lys409Asn

Exon rankExon 9 of 15

missense

Prot: NP_001070707.1

RNF214 NM_001278249.2

HGVSc / HGVSpc.762G>Cp.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>C p.Lys409Asn	missense	Exon 9 of 15	Prot: ENSP00000300650
	RNF214 ENST00000531452.6	TSL:1	c.1227G>C p.Lys409Asn	missense	Exon 9 of 15	Prot: ENSP00000431643
	RNF214 ENST00000852075.2		c.1227G>C p.Lys409Asn	missense	Exon 9 of 15	Prot: ENSP00000522134

RNF214 ENST00000300650.9

MANE Select

HGVSc / HGVSpc.1227G>Cp.Lys409Asn

Exon rankExon 9 of 15

missense

Prot: ENSP00000300650

RNF214 ENST00000531452.6

TSL:1

HGVSc / HGVSpc.1227G>Cp.Lys409Asn

Exon rankExon 9 of 15

missense

Prot: ENSP00000431643

RNF214 ENST00000852075.2

HGVSc / HGVSpc.1227G>Cp.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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 exome Warning	AF: 6.86e-7	AC:1	Hom:0	AN:1458170	Cov:29
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:30

Showing 3 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000671 *	1	1490	0.00 *	0	7190

Showing 1 cohortAllele count / allele number. *AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
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
FuncVEP CTI	Benign	0.029
GPN-Star LLR	N/A	-6.4
GPN-Star score	N/A	6.4
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.14	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	0.041
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	0.040
SpliceAI score (max)	Benign	0.040	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