11-117281395-G-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_207343.4(RNF214):​c.1227G>T​(p.Lys409Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,610,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.945

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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.034347713).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF214	NM_207343.4	c.1227G>T	p.Lys409Asn	missense_variant	Exon 9 of 15	ENST00000300650.9	NP_997226.2
RNF214	NM_001077239.2	c.1227G>T	p.Lys409Asn	missense_variant	Exon 9 of 15		NP_001070707.1
RNF214	NM_001278249.2	c.762G>T	p.Lys254Asn	missense_variant	Exon 9 of 15		NP_001265178.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF214	ENST00000300650.9	c.1227G>T	p.Lys409Asn	missense_variant	Exon 9 of 15	1	NM_207343.4	ENSP00000300650.4

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152004 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000581

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: 0.0000962 AC: 24 AN: 249464 AF XY: 0.0000739

Gnomad AFR exome AF: 0.000387

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000835

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1458170 Hom.: 0 Cov.: 29 AF XY: 0.0000289 AC XY: 21 AN XY: 725752

Gnomad4 AFR exome AF: 0.000269 AC: 9 AN: 33414

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44714

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26116

Gnomad4 EAS exome AF: 0.000277 AC: 11 AN: 39680

Gnomad4 SAS exome AF: 0.0000348 AC: 3 AN: 86150

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53398

Gnomad4 NFE exome AF: 9.02e-7 AC: 1 AN: 1108656

Gnomad4 Remaining exome AF: 0.000282 AC: 17 AN: 60280

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152122 Hom.: 0 Cov.: 30 AF XY: 0.000108 AC XY: 8 AN XY: 74340

Gnomad4 AFR AF: 0.000458 AC: 0.000457699 AN: 0.000457699

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000582 AC: 0.000582072 AN: 0.000582072

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000350 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1227G>T (p.K409N) alteration is located in exon 9 (coding exon 8) of the RNF214 gene. This alteration results from a G to T substitution at nucleotide position 1227, causing the lysine (K) at amino acid position 409 to be replaced by an asparagine (N). 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	0.38
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T;.;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.092
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.90	D;D;.;D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.034	T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.34	N;.;N;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.92	N;N;N;N
REVEL	Benign	0.042
Sift	Uncertain	0.014	D;D;D;D
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.59	P;.;P;.
Vest4		0.18
MutPred		0.32		Gain of ubiquitination at K408 (P = 0.0982);.;Gain of ubiquitination at K408 (P = 0.0982);.;
MVP		0.22
MPC		0.89
ClinPred		0.033	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)		0.080		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs377379346; hg19: chr11-117152111;