NM_032194.3:c.401A>T

Variant names:

• chr6-111008045-A-T
• rs754224144
• NM_032194.3:c.401A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032194.3(RPF2):​c.401A>T​(p.Lys134Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000253 in 1,581,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RPF2 NM_032194.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.25
• Publications: 0 publications found

Genes affected

RPF2 (HGNC:20870): (ribosome production factor 2 homolog) Enables 5S rRNA binding activity. Involved in protein localization to nucleolus; regulation of signal transduction by p53 class mediator; and ribosomal large subunit biogenesis. Located in chromosome; nucleolus; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032194.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPF2	NM_032194.3	MANE Select	c.401A>T	p.Lys134Ile	missense	Exon 7 of 10	NP_115570.1	Q9H7B2
	RPF2	NM_001289111.2		c.212A>T	p.Lys71Ile	missense	Exon 6 of 9	NP_001276040.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPF2	ENST00000441448.7	TSL:1 MANE Select	c.401A>T	p.Lys134Ile	missense	Exon 7 of 10	ENSP00000402338.2	Q9H7B2
	RPF2	ENST00000607388.1	TSL:1	n.*183A>T		non_coding_transcript_exon	Exon 6 of 9	ENSP00000476081.1	U3KQN5
	RPF2	ENST00000607388.1	TSL:1	n.*183A>T		3_prime_UTR	Exon 6 of 9	ENSP00000476081.1	U3KQN5

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150618 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000295

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000873 AC: 2 AN: 229084 AF XY: 0.0000161

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1431292 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 711012

African (AFR) AF: 0.00 AC: 0 AN: 31712

American (AMR) AF: 0.00 AC: 0 AN: 39400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25442

East Asian (EAS) AF: 0.00 AC: 0 AN: 38892

South Asian (SAS) AF: 0.00 AC: 0 AN: 78676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52670

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4658

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1100868

Other (OTH) AF: 0.00 AC: 0 AN: 58974

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150618 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73446

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41010

American (AMR) AF: 0.00 AC: 0 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67718

Other (OTH) AF: 0.00 AC: 0 AN: 2070

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000602 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.3
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.61
MutPred		0.56		Loss of methylation at K134 (P = 2e-04)
MVP		0.35
MPC		0.91
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.95
gMVP		0.81
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs754224144; hg19: chr6-111329248;