rs11190812

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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.

Frequency

Genomes: 𝑓 0.032 ( 129 hom., cov: 34)

Exomes 𝑓: 0.038 ( 1296 hom. )

Consequence

KAZALD1
NM_030929.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.73

Publications

15 publications found

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]

KAZALD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 129 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030929.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KAZALD1	NM_030929.5	MANE Select	c.707G>A	p.Gly236Asp	missense	Exon 4 of 5	NP_112191.2
KAZALD1	NM_001319303.2		c.293G>A	p.Gly98Asp	missense	Exon 4 of 6	NP_001306232.1
KAZALD1	NR_135067.2		n.323G>A		non_coding_transcript_exon	Exon 3 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KAZALD1	ENST00000370200.6	TSL:1 MANE Select	c.707G>A	p.Gly236Asp	missense	Exon 4 of 5	ENSP00000359219.6
KAZALD1	ENST00000477267.1	TSL:5	n.222G>A		non_coding_transcript_exon	Exon 3 of 5
KAZALD1	ENST00000477979.5	TSL:3	n.363G>A		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes

AF:

0.0323

AC:

4919

AN:

152190

Hom.:

129

Cov.:

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

GnomAD2 exomes

AF:

0.0376

AC:

9457

AN:

251228

AF XY:

0.0374

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 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.:

AF XY:

0.0377

AC XY:

27435

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.00582

AC:

195

AN:

33480

American (AMR)

AF:

0.0508

AC:

2271

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0206

AC:

539

AN:

26136

East Asian (EAS)

AF:

0.000176

AC:

AN:

39700

South Asian (SAS)

AF:

0.0163

AC:

1403

AN:

86258

European-Finnish (FIN)

AF:

0.0768

AC:

4098

AN:

53362

Middle Eastern (MID)

AF:

0.00971

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0408

AC:

45328

AN:

1111982

Other (OTH)

AF:

0.0343

AC:

2069

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

3166

6332

9499

12665

15831

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1606

3212

4818

6424

8030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0323

AC:

4918

AN:

152308

Hom.:

129

Cov.:

AF XY:

0.0337

AC XY:

2513

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00674

AC:

280

AN:

41568

American (AMR)

AF:

0.0506

AC:

775

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

AN:

3472

East Asian (EAS)

AF:

0.000578

AC:

AN:

5188

South Asian (SAS)

AF:

0.0128

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0792

AC:

841

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0415

AC:

2824

AN:

68004

Other (OTH)

AF:

0.0293

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

227

455

682

910

1137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0366

Hom.:

547

Bravo

AF:

0.0288

TwinsUK

AF:

0.0391

AC:

145

ALSPAC

AF:

0.0353

AC:

136

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.0434

AC:

373

ExAC

AF:

0.0374

AC:

4541

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.0397

EpiControl

AF:

0.0375

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.065

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0039

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.3

PhyloP100

5.7

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-4.5

REVEL

Benign

0.26

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0090

Polyphen

0.99

Vest4

0.24

MPC

1.2

ClinPred

0.014

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.82

gMVP

0.78

Mutation Taster

=87/13

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over