8-61576775-C-T

Variant names:

• chr8-61576775-C-T
• rs16927574
• NM_004318.4:c.1146G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004318.4(ASPH):​c.1146G>A​(p.Ala382Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0764 in 1,605,954 control chromosomes in the GnomAD database, including 6,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (925 hom., cov: 32)
  • Exomes 𝑓: 0.075 (5226 hom.)
• Consequence: ASPH NM_004318.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.953
• Publications: 15 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 8-61576775-C-T is Benign according to our data. Variant chr8-61576775-C-T is described in ClinVar as Benign. ClinVar VariationId is 1192481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.953 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.258 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPH	NM_004318.4	MANE Select	c.1146G>A	p.Ala382Ala	synonymous	Exon 16 of 25	NP_004309.2
	ASPH	NM_001413844.1		c.1146G>A	p.Ala382Ala	synonymous	Exon 16 of 26	NP_001400773.1
	ASPH	NM_001413845.1		c.1191G>A	p.Ala397Ala	synonymous	Exon 17 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.1146G>A	p.Ala382Ala	synonymous	Exon 16 of 25	ENSP00000368767.4	Q12797-1
	ASPH	ENST00000950798.1		c.1716G>A	p.Ala572Ala	synonymous	Exon 17 of 26	ENSP00000620857.1
	ASPH	ENST00000887974.1		c.1146G>A	p.Ala382Ala	synonymous	Exon 16 of 26	ENSP00000558033.1

Frequencies

GnomAD3 genomes AF: 0.0945 AC: 14371 AN: 152066 Hom.: 920 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.0505

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.0836

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.0759

Gnomad FIN AF: 0.0240

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0631

Gnomad OTH AF: 0.0995

GnomAD2 exomes AF: 0.0887 AC: 22235 AN: 250694 AF XY: 0.0851

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.0968

Gnomad ASJ exome AF: 0.0863

Gnomad EAS exome AF: 0.269

Gnomad FIN exome AF: 0.0267

Gnomad NFE exome AF: 0.0672

Gnomad OTH exome AF: 0.0856

GnomAD4 exome AF: 0.0745 AC: 108372 AN: 1453770 Hom.: 5226 Cov.: 30 AF XY: 0.0742 AC XY: 53673 AN XY: 723034

African (AFR) AF: 0.134 AC: 4477 AN: 33386

American (AMR) AF: 0.0988 AC: 4397 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.0851 AC: 2211 AN: 25972

East Asian (EAS) AF: 0.276 AC: 10912 AN: 39572

South Asian (SAS) AF: 0.0722 AC: 6097 AN: 84482

European-Finnish (FIN) AF: 0.0278 AC: 1472 AN: 52938

Middle Eastern (MID) AF: 0.0867 AC: 497 AN: 5732

European-Non Finnish (NFE) AF: 0.0662 AC: 73281 AN: 1107188

Other (OTH) AF: 0.0838 AC: 5028 AN: 60002

GnomAD4 genome AF: 0.0945 AC: 14378 AN: 152184 Hom.: 925 Cov.: 32 AF XY: 0.0941 AC XY: 7004 AN XY: 74398

African (AFR) AF: 0.136 AC: 5636 AN: 41514

American (AMR) AF: 0.122 AC: 1865 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0836 AC: 290 AN: 3470

East Asian (EAS) AF: 0.270 AC: 1395 AN: 5174

South Asian (SAS) AF: 0.0751 AC: 362 AN: 4818

European-Finnish (FIN) AF: 0.0240 AC: 254 AN: 10598

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0631 AC: 4293 AN: 68008

Other (OTH) AF: 0.0980 AC: 207 AN: 2112

Alfa AF: 0.0803 Hom.: 1055

Bravo AF: 0.105

Asia WGS AF: 0.139 AC: 484 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.8
DANN	Benign	0.74
PhyloP100		-0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs16927574; hg19: chr8-62489334; COSMIC: COSV65244884; COSMIC: COSV65244884;