rs2882460

Variant names:

• chr8-61613337-C-A
• rs2882460
• NM_004318.4:c.976+5641G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-61613337-C-A
• chr8-61613337-C-G
• chr8-61613337-C-T

Variant summary

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

The NM_004318.4(ASPH):​c.976+5641G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 152,074 control chromosomes in the GnomAD database, including 4,106 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 0.23 (4106 hom., cov: 32)
• Consequence: ASPH NM_004318.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.04
• Publications: 7 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPH	NM_004318.4	MANE Select	c.976+5641G>T		intron	N/A	NP_004309.2
	ASPH	NM_001413844.1		c.976+5641G>T		intron	N/A	NP_001400773.1
	ASPH	NM_001413845.1		c.1021+5641G>T		intron	N/A	NP_001400774.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPH	ENST00000379454.9	TSL:1 MANE Select	c.976+5641G>T		intron	N/A	ENSP00000368767.4
	ASPH	ENST00000541428.5	TSL:2	c.889+5641G>T		intron	N/A	ENSP00000437864.1
	ASPH	ENST00000524173.5	TSL:4	c.352+20346G>T		intron	N/A	ENSP00000479945.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34453 AN: 151956 Hom.: 4103 Cov.: 32

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.223

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

GnomAD4 genome AF: 0.227 AC: 34483 AN: 152074 Hom.: 4106 Cov.: 32 AF XY: 0.227 AC XY: 16849 AN XY: 74336

African (AFR) AF: 0.231 AC: 9582 AN: 41468

American (AMR) AF: 0.235 AC: 3587 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 959 AN: 3466

East Asian (EAS) AF: 0.315 AC: 1628 AN: 5170

South Asian (SAS) AF: 0.358 AC: 1727 AN: 4822

European-Finnish (FIN) AF: 0.164 AC: 1735 AN: 10566

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.212 AC: 14431 AN: 67978

Other (OTH) AF: 0.225 AC: 476 AN: 2116

Alfa AF: 0.214 Hom.: 6480

Bravo AF: 0.229

Asia WGS AF: 0.306 AC: 1067 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.059
DANN	Benign	0.48
PhyloP100		-2.0
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: rs2882460; hg19: chr8-62525896;