rs373811778
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_006846.4(SPINK5):c.1875A>T(p.Arg625Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
SPINK5
NM_006846.4 missense
NM_006846.4 missense
Scores
4
14
Clinical Significance
Conservation
PhyloP100: 1.91
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.08366498).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPINK5 | NM_006846.4 | c.1875A>T | p.Arg625Ser | missense_variant | 20/33 | ENST00000256084.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPINK5 | ENST00000256084.8 | c.1875A>T | p.Arg625Ser | missense_variant | 20/33 | 1 | NM_006846.4 | P2 | |
FBXO38-DT | ENST00000667608.1 | n.1257-19180T>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152202Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000362 AC: 9AN: 248780Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135002
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461578Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727090
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GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74364
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Ichthyosis linearis circumflexa Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2022 | This variant is present in population databases (rs373811778, gnomAD 0.04%). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 529163). This variant has not been reported in the literature in individuals affected with SPINK5-related conditions. This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 625 of the SPINK5 protein (p.Arg625Ser). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;D;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;M
MutationTaster
Benign
N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N
REVEL
Benign
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
D;D;.;D
Vest4
MutPred
Gain of phosphorylation at R625 (P = 0.006);Gain of phosphorylation at R625 (P = 0.006);.;Gain of phosphorylation at R625 (P = 0.006);
MVP
MPC
0.53
ClinPred
T
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at