8-61503614-G-A

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.2127-105C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,119,410 control chromosomes in the GnomAD database, including 15,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (2334 hom., cov: 32)
  • Exomes 𝑓: 0.16 (13651 hom.)
• Consequence: ASPH NM_004318.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.241

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=-0.82).
• BP6: Variant 8-61503614-G-A is Benign according to our data. Variant chr8-61503614-G-A is described in ClinVar as [Benign]. Clinvar id is 1221056.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPH	NM_004318.4	c.2127-105C>T		intron_variant		ENST00000379454.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPH	ENST00000379454.9	c.2127-105C>T		intron_variant		1	NM_004318.4	P3
ASPH	ENST00000541428.5	c.2040-105C>T		intron_variant		2		A2

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24684 AN: 151988 Hom.: 2329 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.0958

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.183

GnomAD4 exome AF: 0.162 AC: 156268 AN: 967304 Hom.: 13651 AF XY: 0.163 AC XY: 77712 AN XY: 478048

Gnomad4 AFR exome AF: 0.160

Gnomad4 AMR exome AF: 0.237

Gnomad4 ASJ exome AF: 0.202

Gnomad4 EAS exome AF: 0.377

Gnomad4 SAS exome AF: 0.201

Gnomad4 FIN exome AF: 0.0932

Gnomad4 NFE exome AF: 0.149

Gnomad4 OTH exome AF: 0.180

GnomAD4 genome AF: 0.162 AC: 24687 AN: 152106 Hom.: 2334 Cov.: 32 AF XY: 0.164 AC XY: 12191 AN XY: 74350

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.228

Gnomad4 ASJ AF: 0.194

Gnomad4 EAS AF: 0.398

Gnomad4 SAS AF: 0.189

Gnomad4 FIN AF: 0.0958

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.180

Alfa AF: 0.144 Hom.: 420

Bravo AF: 0.174

Asia WGS AF: 0.254 AC: 883 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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	4.0
Dann	Benign	0.72

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: rs16918881; hg19: chr8-62416173;