rs11190812

Positions:

• chr10-101064535-G-A
• chr10-101064535-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.73

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]

ACMG classification

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
KAZALD1	NM_030929.5	c.707G>A	p.Gly236Asp	missense_variant	4/5	ENST00000370200.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KAZALD1	ENST00000370200.6	c.707G>A	p.Gly236Asp	missense_variant	4/5	1	NM_030929.5	P1
KAZALD1	ENST00000477267.1	n.222G>A		non_coding_transcript_exon_variant	3/5	5
KAZALD1	ENST00000477979.5	n.363G>A		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes AF: 0.0323 AC: 4919 AN: 152190 Hom.: 129 Cov.: 34

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

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

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

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

Other links and lift over

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