NM_006846.4:c.1437delA
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_006846.4(SPINK5):c.1437delA(p.Glu480LysfsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,574 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
SPINK5
NM_006846.4 frameshift
NM_006846.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.790
Publications
0 publications found
Genes affected
SPINK5 (HGNC:15464): (serine peptidase inhibitor Kazal type 5) This gene encodes a multidomain serine protease inhibitor that contains 15 potential inhibitory domains. The encoded preproprotein is proteolytically processed to generate multiple protein products, which may exhibit unique activities and specificities. These proteins may play a role in skin and hair morphogenesis, as well as anti-inflammatory and antimicrobial protection of mucous epithelia. Mutations in this gene may result in Netherton syndrome, a disorder characterized by ichthyosis, defective cornification, and atopy. This gene is present in a gene cluster on chromosome 5. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-148104956-CA-C is Pathogenic according to our data. Variant chr5-148104956-CA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 529155.Status of the report is criteria_provided_single_submitter, 1 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_006846.4. 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 |
|---|---|---|---|---|---|---|---|---|---|
| SPINK5 | MANE Select | c.1437delA | p.Glu480LysfsTer24 | frameshift | Exon 16 of 33 | NP_006837.2 | Q9NQ38-1 | ||
| SPINK5 | c.1437delA | p.Glu480LysfsTer24 | frameshift | Exon 16 of 34 | NP_001121170.1 | Q9NQ38-3 | |||
| SPINK5 | c.1437delA | p.Glu480LysfsTer24 | frameshift | Exon 16 of 28 | NP_001121171.1 | Q9NQ38-2 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SPINK5 | TSL:1 MANE Select | c.1437delA | p.Glu480LysfsTer24 | frameshift | Exon 16 of 33 | ENSP00000256084.7 | Q9NQ38-1 | ||
| SPINK5 | TSL:1 | c.1437delA | p.Glu480LysfsTer24 | frameshift | Exon 16 of 34 | ENSP00000352936.3 | Q9NQ38-3 | ||
| SPINK5 | TSL:1 | c.1437delA | p.Glu480LysfsTer24 | frameshift | Exon 16 of 28 | ENSP00000381472.1 | Q9NQ38-2 |
Frequencies
GnomAD3 genomes 0.00000658 AC: 1AN: 151992Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
151992
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460582Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726606 show subpopulations
GnomAD4 exome
AF:
AC:
4
AN:
1460582
Hom.:
Cov.:
31
AF XY:
AC XY:
2
AN XY:
726606
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33396
American (AMR)
AF:
AC:
0
AN:
44618
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26106
East Asian (EAS)
AF:
AC:
0
AN:
39606
South Asian (SAS)
AF:
AC:
0
AN:
85980
European-Finnish (FIN)
AF:
AC:
0
AN:
53390
Middle Eastern (MID)
AF:
AC:
0
AN:
5760
European-Non Finnish (NFE)
AF:
AC:
4
AN:
1111398
Other (OTH)
AF:
AC:
0
AN:
60328
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.563
Heterozygous variant carriers
0
1
1
2
2
3
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 0.00000658 AC: 1AN: 151992Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74206 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
151992
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74206
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41386
American (AMR)
AF:
AC:
0
AN:
15240
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5180
South Asian (SAS)
AF:
AC:
0
AN:
4818
European-Finnish (FIN)
AF:
AC:
0
AN:
10582
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
1
AN:
68000
Other (OTH)
AF:
AC:
0
AN:
2086
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
Ichthyosis linearis circumflexa (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.