8-61503410-C-G

Variant names:

• chr8-61503410-C-G
• NM_004318.4:c.2226G>C
• ASPH p.Val742Val

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_004318.4(ASPH):​c.2226G>C​(p.Val742Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. V742V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ASPH NM_004318.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0280
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP7: Synonymous conserved (PhyloP=0.028 with no splicing effect.

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.2226G>C	p.Val742Val	synonymous	Exon 25 of 25	NP_004309.2
	ASPH	NM_001413844.1		c.2307G>C	p.Val769Val	synonymous	Exon 26 of 26	NP_001400773.1
	ASPH	NM_001413845.1		c.2271G>C	p.Val757Val	synonymous	Exon 26 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.2226G>C	p.Val742Val	synonymous	Exon 25 of 25	ENSP00000368767.4	Q12797-1
	ASPH	ENST00000950798.1		c.2796G>C	p.Val932Val	synonymous	Exon 26 of 26	ENSP00000620857.1
	ASPH	ENST00000887974.1		c.2307G>C	p.Val769Val	synonymous	Exon 26 of 26	ENSP00000558033.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.9
DANN	Benign	0.79
PhyloP100		0.028
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr8-62415969;