rs11990408

Variant names:

• chr8-61672436-A-G
• rs11990408
• NM_004318.4:c.322+8532T>C

Variant summary

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

The NM_004318.4(ASPH):​c.322+8532T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 152,002 control chromosomes in the GnomAD database, including 2,829 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 0.19 (2829 hom., cov: 31)
• Consequence: ASPH NM_004318.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.302
• Publications: 8 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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPH	NM_004318.4	c.322+8532T>C		intron_variant	Intron 3 of 24	ENST00000379454.9	NP_004309.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPH	ENST00000379454.9	c.322+8532T>C		intron_variant	Intron 3 of 24	1	NM_004318.4	ENSP00000368767.4

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28553 AN: 151884 Hom.: 2826 Cov.: 31

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.182

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

GnomAD4 genome AF: 0.188 AC: 28583 AN: 152002 Hom.: 2829 Cov.: 31 AF XY: 0.189 AC XY: 14024 AN XY: 74302

African (AFR) AF: 0.169 AC: 7013 AN: 41484

American (AMR) AF: 0.192 AC: 2939 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 832 AN: 3468

East Asian (EAS) AF: 0.221 AC: 1144 AN: 5170

South Asian (SAS) AF: 0.349 AC: 1678 AN: 4812

European-Finnish (FIN) AF: 0.142 AC: 1493 AN: 10548

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12759 AN: 67942

Other (OTH) AF: 0.186 AC: 392 AN: 2110

Alfa AF: 0.196 Hom.: 1777

Bravo AF: 0.188

Asia WGS AF: 0.267 AC: 925 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.0
DANN	Benign	0.74
PhyloP100		0.30
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: rs11990408; hg19: chr8-62584995;