rs879255574

Variant names:

• chr8-61526021-AGGTT-CCC
• rs879255574
• NM_004318.4:c.1852_1856delAACCTinsGGG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_004318.4(ASPH):​c.1852_1856delAACCTinsGGG​(p.Asn618GlyfsTer20) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASPH NM_004318.4 frameshift, missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.69
• Publications: 0 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-61526021-AGGTT-CCC is Pathogenic according to our data. Variant chr8-61526021-AGGTT-CCC is described in ClinVar as Pathogenic. ClinVar VariationId is 137614.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004318.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPH	NM_004318.4	MANE Select	c.1852_1856delAACCTinsGGG	p.Asn618GlyfsTer20	frameshift missense	Exon 22 of 25	NP_004309.2
	ASPH	NM_001413844.1		c.1852_1856delAACCTinsGGG	p.Asn618GlyfsTer20	frameshift missense	Exon 22 of 26	NP_001400773.1
	ASPH	NM_001413845.1		c.1897_1901delAACCTinsGGG	p.Asn633GlyfsTer20	frameshift missense	Exon 23 of 26	NP_001400774.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPH	ENST00000379454.9	TSL:1 MANE Select	c.1852_1856delAACCTinsGGG	p.Asn618GlyfsTer20	frameshift missense	Exon 22 of 25	ENSP00000368767.4	Q12797-1
	ASPH	ENST00000950798.1		c.2422_2426delAACCTinsGGG	p.Asn808GlyfsTer20	frameshift missense	Exon 23 of 26	ENSP00000620857.1
	ASPH	ENST00000887974.1		c.1852_1856delAACCTinsGGG	p.Asn618GlyfsTer20	frameshift missense	Exon 22 of 26	ENSP00000558033.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7
Mutation Taster		=2/198	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs879255574; hg19: chr8-62438580;