chr10-101064326-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_030929.5(KAZALD1):c.577T>C(p.Cys193Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
KAZALD1
NM_030929.5 missense
NM_030929.5 missense
Scores
13
4
2
Clinical Significance
Conservation
PhyloP100: 8.02
Genes affected
KAZALD1 (HGNC:25460): (Kazal type serine peptidase inhibitor domain 1) This gene encodes a secreted member of the insulin growth factor-binding protein (IGFBP) superfamily. The protein contains an insulin growth factor-binding domain in its N-terminal region, a Kazal-type serine protease inhibitor and follistatin-like domain in its central region, and an immunoglobulin-like domain in its C-terminal region. Studies of the mouse ortholog suggest that this protein may function in bone development and bone regeneration. This gene is hypomethylated and over-expressed in high-grade glioma compared to low-grade glioma, and thus the hypomethylated gene may be associated with cell proliferation and the shorter survival of patients with high-grade glioma. It is also one of numerous genes found to be deleted in a novel 5.54 Mb interstitial deletion, which is associated with multiple congenital anomalies. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.961
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KAZALD1 | NM_030929.5 | c.577T>C | p.Cys193Arg | missense_variant | 3/5 | ENST00000370200.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KAZALD1 | ENST00000370200.6 | c.577T>C | p.Cys193Arg | missense_variant | 3/5 | 1 | NM_030929.5 | P1 | |
KAZALD1 | ENST00000470106.1 | n.282T>C | non_coding_transcript_exon_variant | 3/3 | 3 | ||||
KAZALD1 | ENST00000477267.1 | n.92T>C | non_coding_transcript_exon_variant | 2/5 | 5 | ||||
KAZALD1 | ENST00000477979.5 | n.233T>C | non_coding_transcript_exon_variant | 2/4 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152238Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251380Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135876
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461888Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 727244
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152238Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2AN XY: 74378
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 23, 2023 | The c.577T>C (p.C193R) alteration is located in exon 3 (coding exon 2) of the KAZALD1 gene. This alteration results from a T to C substitution at nucleotide position 577, causing the cysteine (C) at amino acid position 193 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of sheet (P = 0.0817);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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