NM_024813.3:c.208A>G

Variant names:

• chr1-92301564-A-G
• rs996326261
• NM_024813.3:c.208A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024813.3(RPAP2):​c.208A>G​(p.Ile70Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000217 in 1,382,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I70N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: RPAP2 NM_024813.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70
• Publications: 0 publications found

Genes affected

RPAP2 (HGNC:25791): (RNA polymerase II associated protein 2) Enables RNA polymerase II CTD heptapeptide repeat phosphatase activity. Involved in dephosphorylation of RNA polymerase II C-terminal domain and snRNA transcription. Located in cytosol and nucleolus. Part of RNA polymerase II, holoenzyme. [provided by Alliance of Genome Resources, Apr 2022]

GLMN (HGNC:14373): (glomulin, FKBP associated protein) This gene encodes a phosphorylated protein that is a member of a Skp1-Cullin-F-box-like complex. The protein is essential for normal development of the vasculature and mutations in this gene have been associated with glomuvenous malformations, also called glomangiomas. Multiple splice variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

GLMN Gene-Disease associations (from GenCC):

• glomuvenous malformation

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18467695).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024813.3. 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
	RPAP2	NM_024813.3	MANE Select	c.208A>G	p.Ile70Val	missense	Exon 3 of 13	NP_079089.2	Q8IXW5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPAP2	ENST00000610020.2	TSL:1 MANE Select	c.208A>G	p.Ile70Val	missense	Exon 3 of 13	ENSP00000476948.1	Q8IXW5-1
	RPAP2	ENST00000957713.1		c.208A>G	p.Ile70Val	missense	Exon 3 of 14	ENSP00000627772.1
	RPAP2	ENST00000957711.1		c.208A>G	p.Ile70Val	missense	Exon 3 of 14	ENSP00000627770.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1382806 Hom.: 0 Cov.: 22 AF XY: 0.00000434 AC XY: 3 AN XY: 690928

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

African (AFR) AF: 0.0000668 AC: 2 AN: 29950

American (AMR) AF: 0.0000286 AC: 1 AN: 34956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24988

East Asian (EAS) AF: 0.00 AC: 0 AN: 36606

South Asian (SAS) AF: 0.00 AC: 0 AN: 78880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1061622

Other (OTH) AF: 0.00 AC: 0 AN: 57296

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0763859), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

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	Benign	0.070
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.028	T
Eigen	Benign	0.098
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.00061	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.7
PrimateAI	Benign	0.42	T
Sift4G	Benign	0.53	T
Polyphen		0.82	P
Vest4		0.20
MutPred		0.39		Gain of catalytic residue at I70 (P = 0.0279)
MVP		0.72
MPC		0.066
ClinPred		0.72	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.027
gMVP		0.14

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

Other links and lift over

dbSNP: rs996326261; hg19: chr1-92767121;