Genetic Variant ASPH:c.1537-116A>G (chr8-61553236-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_004318.4(ASPH):c.1537-116A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 727,684 control chromosomes in the GnomAD database, including 23,201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 9389 hom., cov: 33)

Exomes 𝑓: 0.20 ( 13812 hom. )

Consequence

ASPH
NM_004318.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0160

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]

ASPH links:

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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=-0.9).

BP6

Variant 8-61553236-T-C is Benign according to our data. Variant chr8-61553236-T-C is described in ClinVar as [Benign]. Clinvar id is 1236010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPH	NM_004318.4 link	c.1537-116A>G		intron_variant	Intron 19 of 24	ENST00000379454.9	NP_004309.2	Q12797-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPH	ENST00000379454.9 link	c.1537-116A>G		intron_variant	Intron 19 of 24	1	NM_004318.4	ENSP00000368767.4		Q12797-1
ASPH	ENST00000541428.5 link	c.1450-116A>G		intron_variant	Intron 19 of 24	2		ENSP00000437864.1		Q12797-10

Frequencies

GnomAD3 genomes

AF:

0.304

AC:

46162

AN:

151984

Hom.:

9372

Cov.:

show subpopulations

Gnomad AFR

AF:

0.579

Gnomad AMI

AF:

0.213

Gnomad AMR

AF:

0.258

Gnomad ASJ

AF:

0.215

Gnomad EAS

AF:

0.389

Gnomad SAS

AF:

0.174

Gnomad FIN

AF:

0.137

Gnomad MID

AF:

0.248

Gnomad NFE

AF:

0.182

Gnomad OTH

AF:

0.281

GnomAD4 exome

AF:

0.201

AC:

115697

AN:

575582

Hom.:

13812

AF XY:

0.198

AC XY:

60257

AN XY:

304274

show subpopulations

Gnomad4 AFR exome

AF:

0.571

Gnomad4 AMR exome

AF:

0.211

Gnomad4 ASJ exome

AF:

0.218

Gnomad4 EAS exome

AF:

0.391

Gnomad4 SAS exome

AF:

0.162

Gnomad4 FIN exome

AF:

0.143

Gnomad4 NFE exome

AF:

0.179

Gnomad4 OTH exome

AF:

0.217

GnomAD4 genome

AF:

0.304

AC:

46218

AN:

152102

Hom.:

9389

Cov.:

AF XY:

0.299

AC XY:

22236

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.579

Gnomad4 AMR

AF:

0.258

Gnomad4 ASJ

AF:

0.215

Gnomad4 EAS

AF:

0.388

Gnomad4 SAS

AF:

0.172

Gnomad4 FIN

AF:

0.137

Gnomad4 NFE

AF:

0.182

Gnomad4 OTH

AF:

0.281

Alfa

AF:

0.202

Hom.:

5429

Bravo

AF:

0.325

Asia WGS

AF:

0.260

AC:

903

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

2.7

DANN

Benign

0.47

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over