rs7812327

Variant names:

• chr8-61641853-C-T
• rs7812327
• NM_004318.4:c.790+1035G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004318.4(ASPH):​c.790+1035G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 151,972 control chromosomes in the GnomAD database, including 8,630 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.34 (8630 hom., cov: 32)
• Consequence: ASPH NM_004318.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.433
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPH	NM_004318.4	c.790+1035G>A		intron_variant	Intron 10 of 24	ENST00000379454.9	NP_004309.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPH	ENST00000379454.9	c.790+1035G>A		intron_variant	Intron 10 of 24	1	NM_004318.4	ENSP00000368767.4

Frequencies

GnomAD3 genomes AF: 0.336 AC: 51001 AN: 151854 Hom.: 8615 Cov.: 32

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.314

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.336 AC: 51071 AN: 151972 Hom.: 8630 Cov.: 32 AF XY: 0.336 AC XY: 24965 AN XY: 74264

African (AFR) AF: 0.374 AC: 15511 AN: 41442

American (AMR) AF: 0.322 AC: 4911 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1179 AN: 3470

East Asian (EAS) AF: 0.257 AC: 1326 AN: 5164

South Asian (SAS) AF: 0.377 AC: 1816 AN: 4812

European-Finnish (FIN) AF: 0.322 AC: 3402 AN: 10552

Middle Eastern (MID) AF: 0.288 AC: 84 AN: 292

European-Non Finnish (NFE) AF: 0.321 AC: 21813 AN: 67954

Other (OTH) AF: 0.320 AC: 676 AN: 2112

Alfa AF: 0.324 Hom.: 13829

Bravo AF: 0.334

Asia WGS AF: 0.319 AC: 1108 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.9
DANN	Benign	0.74
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7812327; hg19: chr8-62554412;