rs201824659
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_019023.5(PRMT7):c.1056-1G>T variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000129 in 1,613,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
PRMT7
NM_019023.5 splice_acceptor, intron
NM_019023.5 splice_acceptor, intron
Scores
3
2
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.86
Genes affected
PRMT7 (HGNC:25557): (protein arginine methyltransferase 7) This gene encodes a member of the protein arginine N-methyltransferase family of proteins. The encoded enzyme transfers single methyl groups to arginine residues to generate monomethylarginines on histone proteins as well as other protein substrates. This enzyme plays a role in a wide range of biological processes, including neuronal differentiation, male germ line imprinting, small nuclear ribonucleoprotein biogenesis, and regulation of the Wnt signaling pathway. Mutations in this gene underlie multiple related syndromes in human patients characterized by intellectual disability, short stature and other features. The encoded protein may promote breast cancer cell invasion and metastasis in human patients. [provided by RefSeq, May 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.6, offset of 10, new splice context is: cctggcctatccctgaaaAGaat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-68346144-G-T is Pathogenic according to our data. Variant chr16-68346144-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 266024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-68346144-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PRMT7 | NM_019023.5 | c.1056-1G>T | splice_acceptor_variant, intron_variant | ENST00000441236.3 | NP_061896.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PRMT7 | ENST00000441236.3 | c.1056-1G>T | splice_acceptor_variant, intron_variant | 1 | NM_019023.5 | ENSP00000409324.2 |
Frequencies
GnomAD3 genomes 0.0000723 AC: 11AN: 152138Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000679 AC: 17AN: 250392Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135362
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GnomAD4 exome AF: 0.000135 AC: 197AN: 1461216Hom.: 0 Cov.: 31 AF XY: 0.000127 AC XY: 92AN XY: 726888
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GnomAD4 genome 0.0000723 AC: 11AN: 152138Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74328
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Short stature-brachydactyly-obesity-global developmental delay syndrome Pathogenic:3Other:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 03, 2020 | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 12, 2023 | Variant summary: PRMT7 c.1056-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 3' acceptor site. Two predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.8e-05 in 250392 control chromosomes. c.1056-1G>T has been reported in the literature in multiple individuals affected with Short Stature, Brachydactyly, Intellectual Developmental Disability, And Seizures (Cali_2023, Akawi_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26437029, 36399134). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as pathogenic/likely pathogenic (n=5) and benign (n=1) . Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 26, 2019 | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 31, 2021 | This sequence change affects an acceptor splice site in intron 10 of the PRMT7 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PRMT7 are known to be pathogenic (PMID: 26437029, 27718516). This variant is present in population databases (rs201824659, ExAC 0.01%). Disruption of this splice site has been observed in individual(s) with intellectual disability, obesity, and shortened phalanges (PMID: 2643702). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 266024). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 20, 2024 | Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22527104, 30513135, 30006058, 26437029, 28902392, 31589614, 36399134) - |
Neurodevelopmental abnormality Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine | Jun 04, 2020 | - - |
PRMT7-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 30, 2024 | The PRMT7 c.1056-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant in the homozygous or along with a second allele in this gene has been reported multiple individuals with pseudohypoparathyroidism (Akawi et al. 2015. PubMed ID: 26437029; Table S1, Cali et al. 2022. PubMed ID: 36399134). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in PRMT7 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 11
DS_AL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at