Genetic Variant RNF214:c.*1026G>T (chr11-117286177-G-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_207343.4(RNF214):c.*1026G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00685 in 152,674 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0069 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0069 ( 0 hom. )

Consequence

RNF214
NM_207343.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.331

Publications

17 publications found

Variant links:

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]

RNF214 links:

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]

BACE1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BS2

High Homozygotes in GnomAd4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF214	NM_207343.4 link	c.*1026G>T		3_prime_UTR_variant	Exon 15 of 15	ENST00000300650.9	NP_997226.2	Q8ND24-1A0A024R3D4
BACE1	NM_012104.6 link	c.*3389C>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000313005.11	NP_036236.1	P56817-1A0A024R3D7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF214	ENST00000300650.9 link	c.*1026G>T		3_prime_UTR_variant	Exon 15 of 15	1	NM_207343.4	ENSP00000300650.4		Q8ND24-1
BACE1	ENST00000313005.11 link	c.*3389C>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_012104.6	ENSP00000318585.6		P56817-1

Frequencies

GnomAD3 genomes

AF:

0.00686

AC:

1043

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00198

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0112

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.00716

GnomAD4 exome

AF:

0.00691

AC:

AN:

434

Hom.:

Cov.:

AF XY:

0.00769

AC XY:

AN XY:

260

show subpopulations

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

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00708

AC:

AN:

424

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000096912), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.358

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00685

AC:

1043

AN:

152240

Hom.:

Cov.:

AF XY:

0.00627

AC XY:

467

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00197

AC:

AN:

41536

American (AMR)

AF:

0.00490

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.00124

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0112

AC:

119

AN:

10600

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0107

AC:

728

AN:

68000

Other (OTH)

AF:

0.00709

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

102

154

205

256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000326

Hom.:

125

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.1

(source)

DANN

Benign

0.72

PhyloP100

0.33

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over