chr6-110997243-C-T

Variant names:

• chr6-110997243-C-T
• rs1396882383
• NM_032194.3:c.295C>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.295C>T​(p.Arg99Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,596,202 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: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: RPF2 NM_032194.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.553
• 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, 0.769

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.295C>T	p.Arg99Trp	missense	Exon 5 of 10	NP_115570.1	Q9H7B2
	RPF2	NM_001289111.2		c.106C>T	p.Arg36Trp	missense	Exon 4 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.295C>T	p.Arg99Trp	missense	Exon 5 of 10	ENSP00000402338.2	Q9H7B2
	RPF2	ENST00000607388.1	TSL:1	n.*77C>T		non_coding_transcript_exon	Exon 4 of 9	ENSP00000476081.1	U3KQN5
	RPF2	ENST00000607388.1	TSL:1	n.*77C>T		3_prime_UTR	Exon 4 of 9	ENSP00000476081.1	U3KQN5

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152038 Hom.: 0 Cov.: 32

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000811 AC: 2 AN: 246588 AF XY: 0.0000150

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: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000152 AC: 22 AN: 1444164 Hom.: 0 Cov.: 27 AF XY: 0.0000181 AC XY: 13 AN XY: 719066

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

African (AFR) AF: 0.00 AC: 0 AN: 33100

American (AMR) AF: 0.00 AC: 0 AN: 44464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25852

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4958

European-Non Finnish (NFE) AF: 0.0000182 AC: 20 AN: 1097748

Other (OTH) AF: 0.0000167 AC: 1 AN: 59730

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000206429), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152038 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74252

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		0.55
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MVP		0.62
MPC		0.36
ClinPred		1.0	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.85
Mutation Taster		=32/68	disease causing

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

Other links and lift over

dbSNP: rs1396882383; hg19: chr6-111318446;