8-61503515-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004318.4(ASPH):c.2127-6C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.981 in 1,607,586 control chromosomes in the GnomAD database, including 773,395 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (72216 hom., cov: 33)
  • Exomes 𝑓: 0.98 (701179 hom.)
• Consequence: ASPH NM_004318.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001618
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.56

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 8-61503515-G-A is Benign according to our data. Variant chr8-61503515-G-A is described in ClinVar as [Benign]. Clinvar id is 1192457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-61503515-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPH	NM_004318.4	c.2127-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000379454.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPH	ENST00000379454.9	c.2127-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004318.4	P3
ASPH	ENST00000541428.5	c.2040-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2		A2

Frequencies

GnomAD3 genomes AF: 0.974 AC: 148213 AN: 152216 Hom.: 72164 Cov.: 33

Gnomad AFR AF: 0.953

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.980

Gnomad ASJ AF: 0.984

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 0.965

Gnomad MID AF: 0.994

Gnomad NFE AF: 0.981

Gnomad OTH AF: 0.977

GnomAD3 exomes AF: 0.983 AC: 239872 AN: 244032 Hom.: 117904 AF XY: 0.984 AC XY: 129916 AN XY: 132032

Gnomad AFR exome AF: 0.953

Gnomad AMR exome AF: 0.990

Gnomad ASJ exome AF: 0.988

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.999

Gnomad FIN exome AF: 0.965

Gnomad NFE exome AF: 0.981

Gnomad OTH exome AF: 0.984

GnomAD4 exome AF: 0.982 AC: 1428491 AN: 1455252 Hom.: 701179 Cov.: 45 AF XY: 0.982 AC XY: 710523 AN XY: 723342

Gnomad4 AFR exome AF: 0.950

Gnomad4 AMR exome AF: 0.989

Gnomad4 ASJ exome AF: 0.986

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 0.968

Gnomad4 NFE exome AF: 0.981

Gnomad4 OTH exome AF: 0.979

GnomAD4 genome AF: 0.974 AC: 148324 AN: 152334 Hom.: 72216 Cov.: 33 AF XY: 0.973 AC XY: 72462 AN XY: 74490

Gnomad4 AFR AF: 0.953

Gnomad4 AMR AF: 0.980

Gnomad4 ASJ AF: 0.984

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 0.965

Gnomad4 NFE AF: 0.981

Gnomad4 OTH AF: 0.977

Alfa AF: 0.979 Hom.: 33873

Bravo AF: 0.973

Asia WGS AF: 0.995 AC: 3459 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2018	- -

Facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	11
Dann	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.13
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

Publications

LitVar

Other links and lift over

dbSNP: rs7005617; hg19: chr8-62416074;