8-61503509-C-G

Variant names:

• chr8-61503509-C-G
• rs769377583
• NM_004318.4:c.2127G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004318.4(ASPH):​c.2127G>C​(p.Lys709Asn) variant causes a missense, splice region 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. 14/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ASPH NM_004318.4 missense, splice_region
• Scores: Splicing: ADA: 0.3204
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36780676).

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.2127G>C	p.Lys709Asn	missense splice_region	Exon 25 of 25	NP_004309.2
	ASPH	NM_001413844.1		c.2208G>C	p.Glu736Asp	missense splice_region	Exon 26 of 26	NP_001400773.1
	ASPH	NM_001413845.1		c.2172G>C	p.Lys724Asn	missense splice_region	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.2127G>C	p.Lys709Asn	missense splice_region	Exon 25 of 25	ENSP00000368767.4	Q12797-1
	ASPH	ENST00000950798.1		c.2697G>C	p.Lys899Asn	missense splice_region	Exon 26 of 26	ENSP00000620857.1
	ASPH	ENST00000887974.1		c.2208G>C	p.Glu736Asp	missense splice_region	Exon 26 of 26	ENSP00000558033.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000409 AC: 1 AN: 244354 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000299

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: 1 AN: 1457532 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724760

African (AFR) AF: 0.00 AC: 0 AN: 33292

American (AMR) AF: 0.0000226 AC: 1 AN: 44322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39464

South Asian (SAS) AF: 0.00 AC: 0 AN: 85448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109752

Other (OTH) AF: 0.00 AC: 0 AN: 60200

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.3
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.069
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		0.94	P
Vest4		0.51
MutPred		0.61		Loss of ubiquitination at K709 (P = 0.0167)
MVP		0.25
MPC		0.14
ClinPred		0.67	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.60
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.32
dbscSNV1_RF	Benign	0.45
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.31		Position offset: 0

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

Other links and lift over

dbSNP: rs769377583; hg19: chr8-62416068;