X-119870754-A-G

Position:

• chrX-119870754-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006978.3(RNF113A):​c.860T>C​(p.Leu287Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: RNF113A NM_006978.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.27

Genes affected

RNF113A (HGNC:12974): (ring finger protein 113A) This intronless gene encodes a protein which contains a C3H1-type zinc finger domain and a C3HC4 Ring-type (Really Interesting New Gene-type) zinc finger domain. The Ring-type zinc finger domain is identified in various tumor suppressors, DNA repair genes and cytokine receptor-associated molecules, and is probably involved in mediating protein-protein interactions. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF113A	NM_006978.3	c.860T>C	p.Leu287Pro	missense_variant	1/1	ENST00000371442.4	NP_008909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF113A	ENST00000371442.4	c.860T>C	p.Leu287Pro	missense_variant	1/1	6	NM_006978.3	ENSP00000360497.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 17, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -

Trichothiodystrophy 5, nonphotosensitive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 18, 2022

The RNF113A c.860T>C (p.Leu287Pro) missense variant results in the substitution of leucine at amino acid position 287 with proline. To our knowledge, this variant has not been reported in the peer-reviewed literature. This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The variant is located in the RING domain, which is associated with ubiquitination (Brickner et al. 2017). In silico tools, including REVEL, consistently predict the variant to have deleterious effect. Based on the available evidence, the c.860T>C (p.Leu287Pro) variant is classified as variant of uncertain significance for trichothiodystrophy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.8	M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.80		Loss of stability (P = 0.0147);
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-119004717;