chr8-61708280-C-T

Variant names:

• chr8-61708280-C-T
• rs11787089
• NM_004318.4:c.103+5989G>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.103+5989G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 152,146 control chromosomes in the GnomAD database, including 1,896 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 0.15 (1896 hom., cov: 33)
• Consequence: ASPH NM_004318.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.186
• Publications: 6 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPH	NM_004318.4	c.103+5989G>A		intron_variant	Intron 1 of 24	ENST00000379454.9	NP_004309.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPH	ENST00000379454.9	c.103+5989G>A		intron_variant	Intron 1 of 24	1	NM_004318.4	ENSP00000368767.4

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23453 AN: 152028 Hom.: 1895 Cov.: 33

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.153

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

GnomAD4 genome AF: 0.154 AC: 23468 AN: 152146 Hom.: 1896 Cov.: 33 AF XY: 0.155 AC XY: 11553 AN XY: 74376

African (AFR) AF: 0.154 AC: 6402 AN: 41490

American (AMR) AF: 0.136 AC: 2085 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 673 AN: 3472

East Asian (EAS) AF: 0.182 AC: 942 AN: 5182

South Asian (SAS) AF: 0.297 AC: 1435 AN: 4832

European-Finnish (FIN) AF: 0.109 AC: 1150 AN: 10588

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.149 AC: 10144 AN: 67980

Other (OTH) AF: 0.156 AC: 330 AN: 2114

Alfa AF: 0.159 Hom.: 1159

Bravo AF: 0.153

Asia WGS AF: 0.234 AC: 812 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.23
PhyloP100		-0.19
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: rs11787089; hg19: chr8-62620839;