5-148064082-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006846.4(SPINK5):​c.38C>A​(p.Ala13Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SPINK5
NM_006846.4 missense

Scores

5
7
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.07
Variant links:
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 made for transcript

Verdict is Uncertain_significance. Variant got 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
SPINK5NM_006846.4 linkc.38C>A p.Ala13Asp missense_variant Exon 1 of 33 ENST00000256084.8 NP_006837.2 Q9NQ38-1
SPINK5NM_001127698.2 linkc.38C>A p.Ala13Asp missense_variant Exon 1 of 34 NP_001121170.1 Q9NQ38-3
SPINK5NM_001127699.2 linkc.38C>A p.Ala13Asp missense_variant Exon 1 of 28 NP_001121171.1 Q9NQ38-2
SPINK5XM_047416662.1 linkc.38C>A p.Ala13Asp missense_variant Exon 1 of 34 XP_047272618.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPINK5ENST00000256084.8 linkc.38C>A p.Ala13Asp missense_variant Exon 1 of 33 1 NM_006846.4 ENSP00000256084.7 Q9NQ38-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461868
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Ichthyosis linearis circumflexa Uncertain:1
May 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 13 of the SPINK5 protein (p.Ala13Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SPINK5-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.76
BayesDel_addAF
Pathogenic
0.16
D
BayesDel_noAF
Uncertain
-0.010
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.13
T;.;.;.;T
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Benign
0.70
D
LIST_S2
Benign
0.73
T;T;T;T;T
M_CAP
Benign
0.021
T
MetaRNN
Uncertain
0.46
T;T;T;T;T
MetaSVM
Benign
-0.82
T
MutationAssessor
Uncertain
2.8
.;M;M;.;M
PrimateAI
Uncertain
0.51
T
PROVEAN
Pathogenic
-4.8
D;N;N;N;N
REVEL
Benign
0.24
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
0.99, 1.0
.;D;D;.;D
Vest4
0.85, 0.81, 0.90
MutPred
0.54
Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP
0.83
MPC
0.58
ClinPred
0.99
D
GERP RS
3.5
Varity_R
0.19
gMVP
0.60

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-147443645; API