rs374385878
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_004318.4(ASPH):c.2203C>T(p.Arg735Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,612,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
ASPH
NM_004318.4 missense
NM_004318.4 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 5.31
Genes affected
ASPH (HGNC:757): (aspartate beta-hydroxylase) This gene is thought to play an important role in calcium homeostasis. The gene is expressed from two promoters and undergoes extensive alternative splicing. The encoded set of proteins share varying amounts of overlap near their N-termini but have substantial variations in their C-terminal domains resulting in distinct functional properties. The longest isoforms (a and f) include a C-terminal Aspartyl/Asparaginyl beta-hydroxylase domain that hydroxylates aspartic acid or asparagine residues in the epidermal growth factor (EGF)-like domains of some proteins, including protein C, coagulation factors VII, IX, and X, and the complement factors C1R and C1S. Other isoforms differ primarily in the C-terminal sequence and lack the hydroxylase domain, and some have been localized to the endoplasmic and sarcoplasmic reticulum. Some of these isoforms are found in complexes with calsequestrin, triadin, and the ryanodine receptor, and have been shown to regulate calcium release from the sarcoplasmic reticulum. Some isoforms have been implicated in metastasis. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM1
In a binding_site (size 0) in uniprot entity ASPH_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.957
PP5
Variant 8-61503433-G-A is Pathogenic according to our data. Variant chr8-61503433-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 137615.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASPH | NM_004318.4 | c.2203C>T | p.Arg735Trp | missense_variant | 25/25 | ENST00000379454.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASPH | ENST00000379454.9 | c.2203C>T | p.Arg735Trp | missense_variant | 25/25 | 1 | NM_004318.4 | P3 | |
ASPH | ENST00000541428.5 | c.2116C>T | p.Arg706Trp | missense_variant | 25/25 | 2 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152188Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000243 AC: 6AN: 247216Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 133820
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GnomAD4 exome AF: 0.0000246 AC: 36AN: 1460614Hom.: 0 Cov.: 29 AF XY: 0.0000193 AC XY: 14AN XY: 726610
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152306Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74464
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at