Genetic Variant NM_183381.3:c.44T>A (chr3-149846070-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_183381.3(RNF13):c.44T>A(p.Val15Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,452 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RNF13
NM_183381.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.19

Variant links:

Genes affected

RNF13 (HGNC:10057): (ring finger protein 13) The protein encoded by this gene contains a RING zinc finger, a motif known to be involved in protein-protein interactions. The specific function of this gene has not yet been determined. Alternatively spliced transcript variants that encode the same protein have been reported. A pseudogene, which is also located on chromosome 3, has been defined for this gene. [provided by RefSeq, Jul 2008]

RNF13 links:

ANKUB1 (HGNC:29642): (ankyrin repeat and ubiquitin domain containing 1)

ANKUB1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF13	NM_183381.3 link	c.44T>A	p.Val15Asp	missense_variant	Exon 2 of 10	ENST00000392894.8	NP_899237.1	O43567-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF13	ENST00000392894.8 link	c.44T>A	p.Val15Asp	missense_variant	Exon 2 of 10	1	NM_183381.3	ENSP00000376628.3		O43567-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460452

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726572

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with RNF13-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 15 of the RNF13 protein (p.Val15Asp). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.020

T;T;.;T;.;.;T;T

Eigen

Benign

-0.039

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.95

.;D;D;D;D;D;D;D

M_CAP

Benign

0.0094

MetaRNN

Uncertain

0.52

D;D;D;D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;N;.;.;.;.;.;.

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.4

N;N;N;D;N;N;N;N

REVEL

Benign

0.17

Sift

Uncertain

0.0010

D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;D;D;D

Polyphen

0.066

B;B;.;.;.;.;.;.

Vest4

0.81

MutPred

0.67

Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);

MVP

0.55

MPC

0.31

ClinPred

0.74

GERP RS

5.6

Varity_R

0.54

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over