8-61503515-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004318.4(ASPH):​c.2127-6C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.981 in 1,607,586 control chromosomes in the GnomAD database, including 773,395 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.97 ( 72216 hom., cov: 33)
Exomes 𝑓: 0.98 ( 701179 hom. )

Consequence

ASPH
NM_004318.4 splice_region, splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.0001618
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.56
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.53).
BP6
Variant 8-61503515-G-A is Benign according to our data. Variant chr8-61503515-G-A is described in ClinVar as [Benign]. Clinvar id is 1192457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-61503515-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ASPHNM_004318.4 linkuse as main transcriptc.2127-6C>T splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000379454.9 NP_004309.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ASPHENST00000379454.9 linkuse as main transcriptc.2127-6C>T splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1 NM_004318.4 ENSP00000368767 P3Q12797-1
ASPHENST00000541428.5 linkuse as main transcriptc.2040-6C>T splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 2 ENSP00000437864 A2Q12797-10

Frequencies

GnomAD3 genomes
AF:
0.974
AC:
148213
AN:
152216
Hom.:
72164
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.953
Gnomad AMI
AF:
1.00
Gnomad AMR
AF:
0.980
Gnomad ASJ
AF:
0.984
Gnomad EAS
AF:
1.00
Gnomad SAS
AF:
0.999
Gnomad FIN
AF:
0.965
Gnomad MID
AF:
0.994
Gnomad NFE
AF:
0.981
Gnomad OTH
AF:
0.977
GnomAD3 exomes
AF:
0.983
AC:
239872
AN:
244032
Hom.:
117904
AF XY:
0.984
AC XY:
129916
AN XY:
132032
show subpopulations
Gnomad AFR exome
AF:
0.953
Gnomad AMR exome
AF:
0.990
Gnomad ASJ exome
AF:
0.988
Gnomad EAS exome
AF:
1.00
Gnomad SAS exome
AF:
0.999
Gnomad FIN exome
AF:
0.965
Gnomad NFE exome
AF:
0.981
Gnomad OTH exome
AF:
0.984
GnomAD4 exome
AF:
0.982
AC:
1428491
AN:
1455252
Hom.:
701179
Cov.:
45
AF XY:
0.982
AC XY:
710523
AN XY:
723342
show subpopulations
Gnomad4 AFR exome
AF:
0.950
Gnomad4 AMR exome
AF:
0.989
Gnomad4 ASJ exome
AF:
0.986
Gnomad4 EAS exome
AF:
1.00
Gnomad4 SAS exome
AF:
0.999
Gnomad4 FIN exome
AF:
0.968
Gnomad4 NFE exome
AF:
0.981
Gnomad4 OTH exome
AF:
0.979
GnomAD4 genome
AF:
0.974
AC:
148324
AN:
152334
Hom.:
72216
Cov.:
33
AF XY:
0.973
AC XY:
72462
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.953
Gnomad4 AMR
AF:
0.980
Gnomad4 ASJ
AF:
0.984
Gnomad4 EAS
AF:
1.00
Gnomad4 SAS
AF:
0.999
Gnomad4 FIN
AF:
0.965
Gnomad4 NFE
AF:
0.981
Gnomad4 OTH
AF:
0.977
Alfa
AF:
0.979
Hom.:
33873
Bravo
AF:
0.973
Asia WGS
AF:
0.995
AC:
3459
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxSep 06, 2018- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 14, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.53
CADD
Benign
11
DANN
Benign
0.83
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00016
dbscSNV1_RF
Benign
0.13
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: rs7005617; hg19: chr8-62416074; API