8-61553236-T-C

Variant names:

• chr8-61553236-T-C
• rs4291265
• NM_004318.4:c.1537-116A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004318.4(ASPH):​c.1537-116A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 727,684 control chromosomes in the GnomAD database, including 23,201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (9389 hom., cov: 33)
  • Exomes 𝑓: 0.20 (13812 hom.)
• Consequence: ASPH NM_004318.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0160
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-61553236-T-C is Benign according to our data. Variant chr8-61553236-T-C is described in ClinVar as Benign. ClinVar VariationId is 1236010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPH	NM_004318.4	c.1537-116A>G		intron_variant	Intron 19 of 24	ENST00000379454.9	NP_004309.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPH	ENST00000379454.9	c.1537-116A>G		intron_variant	Intron 19 of 24	1	NM_004318.4	ENSP00000368767.4
ASPH	ENST00000541428.5	c.1450-116A>G		intron_variant	Intron 19 of 24	2		ENSP00000437864.1

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46162 AN: 151984 Hom.: 9372 Cov.: 33

Gnomad AFR AF: 0.579

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.389

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.281

GnomAD4 exome AF: 0.201 AC: 115697 AN: 575582 Hom.: 13812 AF XY: 0.198 AC XY: 60257 AN XY: 304274

African (AFR) AF: 0.571 AC: 8284 AN: 14512

American (AMR) AF: 0.211 AC: 4943 AN: 23464

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 3102 AN: 14232

East Asian (EAS) AF: 0.391 AC: 12403 AN: 31710

South Asian (SAS) AF: 0.162 AC: 7517 AN: 46460

European-Finnish (FIN) AF: 0.143 AC: 5598 AN: 39070

Middle Eastern (MID) AF: 0.225 AC: 652 AN: 2896

European-Non Finnish (NFE) AF: 0.179 AC: 66982 AN: 374628

Other (OTH) AF: 0.217 AC: 6216 AN: 28610

GnomAD4 genome AF: 0.304 AC: 46218 AN: 152102 Hom.: 9389 Cov.: 33 AF XY: 0.299 AC XY: 22236 AN XY: 74384

African (AFR) AF: 0.579 AC: 24003 AN: 41460

American (AMR) AF: 0.258 AC: 3939 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 748 AN: 3472

East Asian (EAS) AF: 0.388 AC: 2008 AN: 5172

South Asian (SAS) AF: 0.172 AC: 831 AN: 4832

European-Finnish (FIN) AF: 0.137 AC: 1447 AN: 10582

Middle Eastern (MID) AF: 0.260 AC: 76 AN: 292

European-Non Finnish (NFE) AF: 0.182 AC: 12379 AN: 67986

Other (OTH) AF: 0.281 AC: 593 AN: 2112

Alfa AF: 0.224 Hom.: 17189

Bravo AF: 0.325

Asia WGS AF: 0.260 AC: 903 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.7
DANN	Benign	0.47
PhyloP100		-0.016
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: rs4291265; hg19: chr8-62465795;