rs7005617

Variant names:

• chr8-61503515-G-A
• rs7005617
• NM_004318.4:c.2127-6C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-61503515-G-A
• chr8-61503515-G-C
• chr8-61503515-G-T

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.2127-6C>T variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.0001618
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.56
• Publications: 8 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=-0.53).
• BP6: Variant 8-61503515-G-A is Benign according to our data. Variant chr8-61503515-G-A is described in ClinVar as Benign. ClinVar VariationId is 1192457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 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.2127-6C>T		splice_region intron	N/A	NP_004309.2
	ASPH	NM_001413844.1		c.2208-6C>T		splice_region intron	N/A	NP_001400773.1
	ASPH	NM_001413845.1		c.2172-6C>T		splice_region intron	N/A	NP_001400774.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPH	ENST00000379454.9	TSL:1 MANE Select	c.2127-6C>T		splice_region intron	N/A	ENSP00000368767.4	Q12797-1
	ASPH	ENST00000950798.1		c.2697-6C>T		splice_region intron	N/A	ENSP00000620857.1
	ASPH	ENST00000887974.1		c.2208-6C>T		splice_region intron	N/A	ENSP00000558033.1

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

GnomAD2 exomes AF: 0.983 AC: 239872 AN: 244032 AF XY: 0.984

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 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

African (AFR) AF: 0.950 AC: 31565 AN: 33236

American (AMR) AF: 0.989 AC: 43681 AN: 44176

Ashkenazi Jewish (ASJ) AF: 0.986 AC: 25659 AN: 26014

East Asian (EAS) AF: 1.00 AC: 39356 AN: 39356

South Asian (SAS) AF: 0.999 AC: 85076 AN: 85182

European-Finnish (FIN) AF: 0.968 AC: 51540 AN: 53226

Middle Eastern (MID) AF: 0.993 AC: 5695 AN: 5736

European-Non Finnish (NFE) AF: 0.981 AC: 1087060 AN: 1108224

Other (OTH) AF: 0.979 AC: 58859 AN: 60102

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

African (AFR) AF: 0.953 AC: 39605 AN: 41558

American (AMR) AF: 0.980 AC: 15007 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.984 AC: 3417 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5180 AN: 5180

South Asian (SAS) AF: 0.999 AC: 4827 AN: 4832

European-Finnish (FIN) AF: 0.965 AC: 10256 AN: 10624

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 0.981 AC: 66760 AN: 68040

Other (OTH) AF: 0.977 AC: 2068 AN: 2116

Alfa AF: 0.978 Hom.: 34222

Bravo AF: 0.973

Asia WGS AF: 0.995 AC: 3459 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	-0.53
CADD	Benign	11
DANN	Benign	0.83
PhyloP100		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7005617; hg19: chr8-62416074;