Variant 5-64212125-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001113561.2(RNF180):c.196G>A(p.Ala66Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,606,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RNF180
NM_001113561.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.26

Variant links:

Genes affected

RNF180 (HGNC:27752): (ring finger protein 180) Predicted to enable ubiquitin conjugating enzyme binding activity and ubiquitin protein ligase activity. Predicted to be involved in norepinephrine metabolic process; positive regulation of proteasomal ubiquitin-dependent protein catabolic process; and serotonin metabolic process. Predicted to act upstream of or within several processes, including adult behavior; positive regulation of protein ubiquitination; and protein polyubiquitination. Predicted to be located in nuclear envelope. Predicted to be integral component of membrane. Predicted to be intrinsic component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

RNF180 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18183777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF180	NM_001113561.2 linkuse as main transcript	c.196G>A	p.Ala66Thr	missense_variant	3/8	ENST00000389100.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF180	ENST00000389100.9 linkuse as main transcript	c.196G>A	p.Ala66Thr	missense_variant	3/8	1	NM_001113561.2	P1	Q86T96-1
RNF180	ENST00000296615.10 linkuse as main transcript	c.196G>A	p.Ala66Thr	missense_variant	3/5	1			Q86T96-2
RNF180	ENST00000504296.1 linkuse as main transcript	c.196G>A	p.Ala66Thr	missense_variant	3/4	3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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

AF:

6.88e-7

AC:

AN:

1454354

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723970

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2024

The c.196G>A (p.A66T) alteration is located in exon 3 (coding exon 2) of the RNF180 gene. This alteration results from a G to A substitution at nucleotide position 196, causing the alanine (A) at amino acid position 66 to be replaced by a threonine (T). 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

Benign

0.078

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.0057

.;T;.

Eigen

Benign

-0.087

Eigen_PC

Benign

-0.018

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.74

T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.6

M;M;.

MutationTaster

Benign

0.58

D;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.62

N;N;N

REVEL

Benign

0.071

Sift

Benign

0.17

T;T;T

Sift4G

Benign

0.21

T;T;T

Polyphen

0.91

P;B;.

Vest4

0.10

MutPred

0.70

Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);

MVP

0.66

MPC

0.034

ClinPred

0.60

GERP RS

4.1

Varity_R

0.035

gMVP

0.29

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over