Genetic Variant NM_004318.4:c.2127G>A (chr8-61503509-C-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_004318.4(ASPH):c.2127G>A(p.Lys709Lys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ASPH
NM_004318.4 splice_region, synonymous

Scores

Splicing: ADA: 0.006782

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.26

Publications

0 publications found

Variant links:

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

ASPH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP7

Synonymous conserved (PhyloP=1.26 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ASPH	NM_004318.4	MANE Select	c.2127G>A	p.Lys709Lys	splice_region synonymous	Exon 25 of 25	NP_004309.2
ASPH	NM_001413891.1		c.1993G>A	p.Asp665Asn	missense splice_region	Exon 24 of 24	NP_001400820.1
ASPH	NM_001413893.1		c.1990G>A	p.Asp664Asn	missense splice_region	Exon 24 of 24	NP_001400822.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ASPH	ENST00000379454.9	TSL:1 MANE Select	c.2127G>A	p.Lys709Lys	splice_region synonymous	Exon 25 of 25	ENSP00000368767.4	Q12797-1
ASPH	ENST00000950798.1		c.2697G>A	p.Lys899Lys	splice_region synonymous	Exon 26 of 26	ENSP00000620857.1
ASPH	ENST00000887974.1		c.2208G>A	p.Glu736Glu	splice_region synonymous	Exon 26 of 26	ENSP00000558033.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000409

AC:

AN:

244354

AF XY:

0.00000757

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457532

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724760

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33292

American (AMR)

AF:

0.00

AC:

AN:

44322

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26036

East Asian (EAS)

AF:

0.00

AC:

AN:

39464

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85448

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109752

Other (OTH)

AF:

0.00

AC:

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=58/42

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0068

dbscSNV1_RF

Benign

0.19

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over