rs4291265

Positions:

• chr8-61553236-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0160

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]

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 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/exons	MANE	UniProt
ASPH	NM_004318.4	c.1537-116A>G		intron_variant		ENST00000379454.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPH	ENST00000379454.9	c.1537-116A>G		intron_variant		1	NM_004318.4	P3
ASPH	ENST00000541428.5	c.1450-116A>G		intron_variant		2		A2

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46162 AN: 151984 Hom.: 9372 Cov.: 33

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

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.: 33 AF XY: 0.299 AC XY: 22236 AN XY: 74384

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 04, 2018

- -

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

Other links and lift over

dbSNP: rs4291265; hg19: chr8-62465795;