NM_004318.4:c.323-613C>A

Variant names:

• chr8-61654273-G-T
• rs6471969
• NM_004318.4:c.323-613C>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.323-613C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 152,106 control chromosomes in the GnomAD database, including 2,713 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 0.18 (2713 hom., cov: 32)
• Consequence: ASPH NM_004318.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.100
• Publications: 5 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=-0.87).
• 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.323-613C>A		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.323-613C>A		intron_variant	Intron 3 of 24	1	NM_004318.4	ENSP00000368767.4

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27943 AN: 151988 Hom.: 2710 Cov.: 32

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.178

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

GnomAD4 genome AF: 0.184 AC: 27971 AN: 152106 Hom.: 2713 Cov.: 32 AF XY: 0.185 AC XY: 13767 AN XY: 74360

African (AFR) AF: 0.164 AC: 6790 AN: 41468

American (AMR) AF: 0.191 AC: 2914 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 825 AN: 3466

East Asian (EAS) AF: 0.221 AC: 1143 AN: 5182

South Asian (SAS) AF: 0.349 AC: 1685 AN: 4830

European-Finnish (FIN) AF: 0.141 AC: 1495 AN: 10588

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

European-Non Finnish (NFE) AF: 0.182 AC: 12399 AN: 67980

Other (OTH) AF: 0.182 AC: 384 AN: 2108

Alfa AF: 0.192 Hom.: 1633

Bravo AF: 0.183

Asia WGS AF: 0.265 AC: 919 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.0
DANN	Benign	0.35
PhyloP100		0.10
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: rs6471969; hg19: chr8-62566832;