chr1-92346639-A-G

Variant names:

• chr1-92346639-A-G
• rs12125484
• NM_024813.3:c.1688+725A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024813.3(RPAP2):​c.1688+725A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 152,084 control chromosomes in the GnomAD database, including 8,341 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (8341 hom., cov: 32)
• Consequence: RPAP2 NM_024813.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.187
• Publications: 9 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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.832 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPAP2	NM_024813.3	c.1688+725A>G		intron_variant	Intron 11 of 12	ENST00000610020.2	NP_079089.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPAP2	ENST00000610020.2	c.1688+725A>G		intron_variant	Intron 11 of 12	1	NM_024813.3	ENSP00000476948.1
RPAP2	ENST00000477322.1	n.382+725A>G		intron_variant	Intron 3 of 4	2

Frequencies

GnomAD3 genomes AF: 0.296 AC: 45036 AN: 151966 Hom.: 8335 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.853

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.300

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.296 AC: 45042 AN: 152084 Hom.: 8341 Cov.: 32 AF XY: 0.300 AC XY: 22293 AN XY: 74344

African (AFR) AF: 0.131 AC: 5451 AN: 41500

American (AMR) AF: 0.375 AC: 5731 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1197 AN: 3472

East Asian (EAS) AF: 0.853 AC: 4416 AN: 5176

South Asian (SAS) AF: 0.496 AC: 2391 AN: 4818

European-Finnish (FIN) AF: 0.260 AC: 2743 AN: 10566

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.323 AC: 21981 AN: 67952

Other (OTH) AF: 0.308 AC: 652 AN: 2114

Alfa AF: 0.303 Hom.: 1715

Bravo AF: 0.296

Asia WGS AF: 0.580 AC: 2014 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.4
DANN	Benign	0.71
PhyloP100		0.19

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: rs12125484; hg19: chr1-92812196; COSMIC: COSV72101451;