2-7024433-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014746.6(RNF144A):c.574A>G(p.Ile192Val) 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: 33)
• Consequence: RNF144A NM_014746.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.22

Genes affected

RNF144A (HGNC:20457): (ring finger protein 144A) This gene encodes a member of a family of RING finger domain-containing E3 ubiquitin ligases that also includes parkin and parc. The expression of this gene is induced by DNA damage. The encoded protein interacts with the cytoplasmic DNA-dependent protein kinase, catalytic subunit (DNA-PKcs) and promotes its degradation through ubiquitination. The orthologous mouse protein has been shown to interact with a ubiquitin-conjugating enzyme involved in embryonic development. [provided by RefSeq, Mar 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF144A	NM_014746.6	c.574A>G	p.Ile192Val	missense_variant	7/9	ENST00000320892.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF144A	ENST00000320892.11	c.574A>G	p.Ile192Val	missense_variant	7/9	1	NM_014746.6	P1
RNF144A	ENST00000432850.1	c.562A>G	p.Ile188Val	missense_variant	5/7	3
RNF144A	ENST00000467276.5	n.695A>G		non_coding_transcript_exon_variant	4/6	3
RNF144A	ENST00000480970.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2023

The c.574A>G (p.I192V) alteration is located in exon 7 (coding exon 5) of the RNF144A gene. This alteration results from a A to G substitution at nucleotide position 574, causing the isoleucine (I) at amino acid position 192 to be replaced by a valine (V). 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	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.70	P
Vest4		0.59
MutPred		0.78		Loss of sheet (P = 0.0457);
MVP		0.54
MPC		1.2
ClinPred		0.94	D
GERP RS		5.9
Varity_R		0.36
gMVP		0.36

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: chr2-7164564;