rs11190812

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_030929.5(KAZALD1):​c.707G>A​(p.Gly236Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0377 in 1,614,108 control chromosomes in the GnomAD database, including 1,425 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.032 ( 129 hom., cov: 34)
Exomes 𝑓: 0.038 ( 1296 hom. )

Consequence

KAZALD1
NM_030929.5 missense

Scores

4
6
8

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.73
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.003905654).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0323 (4918/152308) while in subpopulation AMR AF= 0.0506 (775/15304). AF 95% confidence interval is 0.0477. There are 129 homozygotes in gnomad4. There are 2513 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 129 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KAZALD1NM_030929.5 linkuse as main transcriptc.707G>A p.Gly236Asp missense_variant 4/5 ENST00000370200.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KAZALD1ENST00000370200.6 linkuse as main transcriptc.707G>A p.Gly236Asp missense_variant 4/51 NM_030929.5 P1Q96I82-1
KAZALD1ENST00000477267.1 linkuse as main transcriptn.222G>A non_coding_transcript_exon_variant 3/55
KAZALD1ENST00000477979.5 linkuse as main transcriptn.363G>A non_coding_transcript_exon_variant 3/43

Frequencies

GnomAD3 genomes
AF:
0.0323
AC:
4919
AN:
152190
Hom.:
129
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00676
Gnomad AMI
AF:
0.00439
Gnomad AMR
AF:
0.0506
Gnomad ASJ
AF:
0.0187
Gnomad EAS
AF:
0.000577
Gnomad SAS
AF:
0.0130
Gnomad FIN
AF:
0.0792
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.0415
Gnomad OTH
AF:
0.0296
GnomAD3 exomes
AF:
0.0376
AC:
9457
AN:
251228
Hom.:
257
AF XY:
0.0374
AC XY:
5072
AN XY:
135796
show subpopulations
Gnomad AFR exome
AF:
0.00591
Gnomad AMR exome
AF:
0.0515
Gnomad ASJ exome
AF:
0.0210
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0148
Gnomad FIN exome
AF:
0.0786
Gnomad NFE exome
AF:
0.0440
Gnomad OTH exome
AF:
0.0357
GnomAD4 exome
AF:
0.0383
AC:
55966
AN:
1461800
Hom.:
1296
Cov.:
31
AF XY:
0.0377
AC XY:
27435
AN XY:
727198
show subpopulations
Gnomad4 AFR exome
AF:
0.00582
Gnomad4 AMR exome
AF:
0.0508
Gnomad4 ASJ exome
AF:
0.0206
Gnomad4 EAS exome
AF:
0.000176
Gnomad4 SAS exome
AF:
0.0163
Gnomad4 FIN exome
AF:
0.0768
Gnomad4 NFE exome
AF:
0.0408
Gnomad4 OTH exome
AF:
0.0343
GnomAD4 genome
AF:
0.0323
AC:
4918
AN:
152308
Hom.:
129
Cov.:
34
AF XY:
0.0337
AC XY:
2513
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.00674
Gnomad4 AMR
AF:
0.0506
Gnomad4 ASJ
AF:
0.0187
Gnomad4 EAS
AF:
0.000578
Gnomad4 SAS
AF:
0.0128
Gnomad4 FIN
AF:
0.0792
Gnomad4 NFE
AF:
0.0415
Gnomad4 OTH
AF:
0.0293
Alfa
AF:
0.0355
Hom.:
300
Bravo
AF:
0.0288
TwinsUK
AF:
0.0391
AC:
145
ALSPAC
AF:
0.0353
AC:
136
ESP6500AA
AF:
0.00658
AC:
29
ESP6500EA
AF:
0.0434
AC:
373
ExAC
AF:
0.0374
AC:
4541
Asia WGS
AF:
0.00779
AC:
27
AN:
3478
EpiCase
AF:
0.0397
EpiControl
AF:
0.0375

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.25
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.065
T
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.92
D
MetaRNN
Benign
0.0039
T
MetaSVM
Benign
-0.57
T
MutationAssessor
Uncertain
2.3
M
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.48
T
PROVEAN
Pathogenic
-4.5
D
REVEL
Benign
0.26
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.0090
D
Polyphen
0.99
D
Vest4
0.24
MPC
1.2
ClinPred
0.014
T
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.82
gMVP
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs11190812; hg19: chr10-102824292; COSMIC: COSV64630140; COSMIC: COSV64630140; API