8-61503614-G-A

Variant names:

• chr8-61503614-G-A
• rs16918881
• NM_004318.4:c.2127-105C>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.2127-105C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,119,410 control chromosomes in the GnomAD database, including 15,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2334 hom., cov: 32)
  • Exomes 𝑓: 0.16 (13651 hom.)
• Consequence: ASPH NM_004318.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.241
• Publications: 4 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=-0.82).
• BP6: Variant 8-61503614-G-A is Benign according to our data. Variant chr8-61503614-G-A is described in ClinVar as Benign. ClinVar VariationId is 1221056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 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.2127-105C>T		intron	N/A	NP_004309.2
	ASPH	NM_001413844.1		c.2208-105C>T		intron	N/A	NP_001400773.1
	ASPH	NM_001413845.1		c.2172-105C>T		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.2127-105C>T		intron	N/A	ENSP00000368767.4	Q12797-1
	ASPH	ENST00000950798.1		c.2697-105C>T		intron	N/A	ENSP00000620857.1
	ASPH	ENST00000887974.1		c.2208-105C>T		intron	N/A	ENSP00000558033.1

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24684 AN: 151988 Hom.: 2329 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.0958

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.183

GnomAD4 exome AF: 0.162 AC: 156268 AN: 967304 Hom.: 13651 AF XY: 0.163 AC XY: 77712 AN XY: 478048

African (AFR) AF: 0.160 AC: 3470 AN: 21704

American (AMR) AF: 0.237 AC: 4356 AN: 18366

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 3266 AN: 16160

East Asian (EAS) AF: 0.377 AC: 11941 AN: 31666

South Asian (SAS) AF: 0.201 AC: 9724 AN: 48276

European-Finnish (FIN) AF: 0.0932 AC: 3215 AN: 34512

Middle Eastern (MID) AF: 0.170 AC: 628 AN: 3694

European-Non Finnish (NFE) AF: 0.149 AC: 112056 AN: 750728

Other (OTH) AF: 0.180 AC: 7612 AN: 42198

GnomAD4 genome AF: 0.162 AC: 24687 AN: 152106 Hom.: 2334 Cov.: 32 AF XY: 0.164 AC XY: 12191 AN XY: 74350

African (AFR) AF: 0.161 AC: 6668 AN: 41488

American (AMR) AF: 0.228 AC: 3485 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 673 AN: 3470

East Asian (EAS) AF: 0.398 AC: 2060 AN: 5170

South Asian (SAS) AF: 0.189 AC: 913 AN: 4822

European-Finnish (FIN) AF: 0.0958 AC: 1015 AN: 10590

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9397 AN: 67972

Other (OTH) AF: 0.180 AC: 381 AN: 2114

Alfa AF: 0.145 Hom.: 428

Bravo AF: 0.174

Asia WGS AF: 0.254 AC: 883 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.0
DANN	Benign	0.72
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs16918881; hg19: chr8-62416173; COSMIC: COSV107354209; COSMIC: COSV107354209;