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. 13/22 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
• 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: Likely_benign. The variant received -4 ACMG points.

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

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

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

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF214	ENST00000300650.9	TSL:1 MANE Select	c.1227G>T	p.Lys409Asn	missense	Exon 9 of 15	ENSP00000300650.4
	RNF214	ENST00000531452.5	TSL:1	c.1227G>T	p.Lys409Asn	missense	Exon 9 of 15	ENSP00000431643.1
	RNF214	ENST00000531287.5	TSL:2	c.762G>T	p.Lys254Asn	missense	Exon 9 of 15	ENSP00000435361.1

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

African (AFR) AF: 0.000269 AC: 9 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: 0.000277 AC: 11 AN: 39680

South Asian (SAS) AF: 0.0000348 AC: 3 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: 0.000282 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

African (AFR) AF: 0.000458 AC: 19 AN: 41512

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000582 AC: 3 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2114

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 v4.9

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
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.092
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.034	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	0.042
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		0.033	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

Other links and lift over

dbSNP: rs377379346; hg19: chr11-117152111;