rs374385878

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

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. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

ASPH
NM_004318.4 missense

Scores

16
2
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 5.31
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 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 [Likely_pathogenic]. Clinvar id is 137615.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ASPHNM_004318.4 linkc.2203C>T p.Arg735Trp missense_variant Exon 25 of 25 ENST00000379454.9 NP_004309.2 Q12797-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ASPHENST00000379454.9 linkc.2203C>T p.Arg735Trp missense_variant Exon 25 of 25 1 NM_004318.4 ENSP00000368767.4 Q12797-1
ASPHENST00000541428.5 linkc.2116C>T p.Arg706Trp missense_variant Exon 25 of 25 2 ENSP00000437864.1 Q12797-10

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152188
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000965
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:
0.0000243
AC:
6
AN:
247216
AF XY:
0.0000149
show subpopulations
Gnomad AFR exome
AF:
0.0000618
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:
0.0000271
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000246
AC:
36
AN:
1460614
Hom.:
0
Cov.:
29
AF XY:
0.0000193
AC XY:
14
AN XY:
726610
show subpopulations
Gnomad4 AFR exome
AF:
0.00
AC:
0
AN:
33430
Gnomad4 AMR exome
AF:
0.00
AC:
0
AN:
44602
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26116
Gnomad4 EAS exome
AF:
0.0000253
AC:
1
AN:
39590
Gnomad4 SAS exome
AF:
0.0000349
AC:
3
AN:
86034
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53350
Gnomad4 NFE exome
AF:
0.0000279
AC:
31
AN:
1111538
Gnomad4 Remaining exome
AF:
0.0000166
AC:
1
AN:
60316
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152306
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.0000962
AC:
0.0000962418
AN:
0.0000962418
Gnomad4 AMR
AF:
0.00
AC:
0
AN:
0
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.0000294
AC:
0.0000293962
AN:
0.0000293962
Gnomad4 OTH
AF:
0.00
AC:
0
AN:
0
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000815
Hom.:
0
Bravo
AF:
0.0000264
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000546
EpiControl
AF:
0.00

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Thoracic aortic aneurysm or dissection Pathogenic:1
Apr 09, 2025
NHS Central & South Genomic Laboratory Hub
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome Pathogenic:1
May 01, 2014
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.89
D;.
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.29
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Uncertain
0.68
D
MutationAssessor
Pathogenic
4.0
H;.
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-7.0
D;D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.98
MVP
0.99
MPC
0.28
ClinPred
1.0
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
gMVP
0.88
Mutation Taster
=7/93
disease causing (ClinVar)

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs374385878; hg19: chr8-62415992; COSMIC: COSV57977390; COSMIC: COSV57977390; API