rs901683870

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_130768.3(ASZ1):​c.727G>T​(p.Gly243*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,426,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

ASZ1
NM_130768.3 stop_gained

Scores

4
2
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.27

Publications

0 publications found
Variant links:
Genes affected
ASZ1 (HGNC:1350): (ankyrin repeat, SAM and basic leucine zipper domain containing 1) Predicted to be involved in gamete generation and piRNA metabolic process. Predicted to be located in cytoplasm. Predicted to be active in pi-body. [provided by Alliance of Genome Resources, Apr 2022]
CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]
CFTR Gene-Disease associations (from GenCC):
  • cystic fibrosis
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
  • congenital bilateral absence of vas deferens
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hereditary chronic pancreatitis
    Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ASZ1NM_130768.3 linkc.727G>T p.Gly243* stop_gained Exon 7 of 13 ENST00000284629.7 NP_570124.1 Q8WWH4-1
ASZ1NM_001301821.2 linkc.727G>T p.Gly243* stop_gained Exon 7 of 13 NP_001288750.1 Q8WWH4-2
ASZ1NM_001301822.2 linkc.103G>T p.Gly35* stop_gained Exon 6 of 12 NP_001288751.1 Q8WWH4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ASZ1ENST00000284629.7 linkc.727G>T p.Gly243* stop_gained Exon 7 of 13 1 NM_130768.3 ENSP00000284629.2 Q8WWH4-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.01e-7
AC:
1
AN:
1426394
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
708902
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
31566
American (AMR)
AF:
0.00
AC:
0
AN:
38548
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
37652
South Asian (SAS)
AF:
0.0000125
AC:
1
AN:
79824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52362
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5636
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1096988
Other (OTH)
AF:
0.00
AC:
0
AN:
58686
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
39
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Uncertain
0.90
D
PhyloP100
2.3
Vest4
0.27
GERP RS
5.7
Mutation Taster
=29/171
disease causing (fs/PTC)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.28
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.28
Position offset: -15

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

Publications

Other links and lift over

dbSNP: rs901683870; hg19: chr7-117023125; COSMIC: COSV52912464; API