19-55763074-G-C

Variant names:

• chr19-55763074-G-C
• NM_001145014.2:c.763G>C

Variant summary

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

The NM_001145014.2(RFPL4A):​c.763G>C​(p.Ala255Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: RFPL4A NM_001145014.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.187

Genes affected

RFPL4A (HGNC:16449): (ret finger protein like 4A) Predicted to enable ubiquitin-protein transferase activity. Predicted to be involved in positive regulation of transcription, DNA-templated. Predicted to be located in nucleus. Predicted to be active in chromatin and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFPL4A	NM_001145014.2	c.763G>C	p.Ala255Pro	missense_variant	Exon 3 of 3	ENST00000434937.3	NP_001138486.1
RFPL4A	XM_011526915.4	c.934G>C	p.Ala312Pro	missense_variant	Exon 4 of 4		XP_011525217.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFPL4A	ENST00000434937.3	c.763G>C	p.Ala255Pro	missense_variant	Exon 3 of 3	5	NM_001145014.2	ENSP00000392936.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 97

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.763G>C (p.A255P) alteration is located in exon 3 (coding exon 2) of the RFPL4A gene. This alteration results from a G to C substitution at nucleotide position 763, causing the alanine (A) at amino acid position 255 to be replaced by a proline (P). 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	0.78
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.29
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.045	D
Polyphen		1.0	D
Vest4		0.25
MutPred		0.85		Gain of disorder (P = 0.0453);
MVP		0.22
MPC		2.1
ClinPred		0.65	D
GERP RS		-4.2
Varity_R		0.60
gMVP		0.52

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: chr19-56274440;