Genetic Variant NM_001382266.1:c.176T>A (chr12-116749933-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001382266.1(RNFT2):c.176T>A(p.Leu59His) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,970 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 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RNFT2
NM_001382266.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.74

Publications

1 publications found

Variant links:

Genes affected

RNFT2 (HGNC:25905): (ring finger protein, transmembrane 2) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in positive regulation of ERAD pathway and protein ubiquitination. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

RNFT2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30251953).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382266.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNFT2	NM_001382266.1	MANE Select	c.176T>A	p.Leu59His	missense	Exon 4 of 11	NP_001369195.1	Q96EX2-1
RNFT2	NM_001109903.2		c.176T>A	p.Leu59His	missense	Exon 4 of 12	NP_001103373.1	Q96EX2-1
RNFT2	NM_032814.4		c.176T>A	p.Leu59His	missense	Exon 4 of 11	NP_116203.2	Q96EX2-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNFT2	ENST00000257575.9	TSL:5 MANE Select	c.176T>A	p.Leu59His	missense	Exon 4 of 11	ENSP00000257575.4	Q96EX2-1
RNFT2	ENST00000392549.7	TSL:5	c.176T>A	p.Leu59His	missense	Exon 4 of 12	ENSP00000376332.2	Q96EX2-1
RNFT2	ENST00000407967.7	TSL:5	c.176T>A	p.Leu59His	missense	Exon 4 of 11	ENSP00000385669.3	Q96EX2-5

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1425982

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

705984

African (AFR)

AF:

0.00

AC:

AN:

32746

American (AMR)

AF:

0.00

AC:

AN:

39300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25438

East Asian (EAS)

AF:

0.00

AC:

AN:

37766

South Asian (SAS)

AF:

0.00

AC:

AN:

81220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50764

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094004

Other (OTH)

AF:

0.00

AC:

AN:

59026

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74218

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41356

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.033

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.022

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

PhyloP100

5.7

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.030

REVEL

Benign

0.10

Sift

Uncertain

0.0090

Sift4G

Benign

0.32

Polyphen

0.94

Vest4

0.50

MutPred

0.19

Loss of stability (P = 0.0151)

MVP

0.082

MPC

0.54

ClinPred

0.74

GERP RS

4.3

Varity_R

0.14

gMVP

0.70

Mutation Taster

=53/47

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over