NM_030929.5:c.211A>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_030929.5(KAZALD1):c.211A>T(p.Arg71Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,577,584 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0092 ( 20 hom., cov: 33)

Exomes 𝑓: 0.00096 ( 33 hom. )

Consequence

KAZALD1
NM_030929.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.252

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037122667).

BP6

Variant 10-101062803-A-T is Benign according to our data. Variant chr10-101062803-A-T is described in ClinVar as [Benign]. Clinvar id is 716217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00921 (1402/152290) while in subpopulation AFR AF= 0.0327 (1358/41564). AF 95% confidence interval is 0.0312. There are 20 homozygotes in gnomad4. There are 641 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KAZALD1	NM_030929.5 link	c.211A>T	p.Arg71Trp	missense_variant	Exon 2 of 5	ENST00000370200.6	NP_112191.2	Q96I82-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KAZALD1	ENST00000370200.6 link	c.211A>T	p.Arg71Trp	missense_variant	Exon 2 of 5	1	NM_030929.5	ENSP00000359219.6	Q96I82-1
KAZALD1	ENST00000470106.1 link	n.44-183A>T		intron_variant	Intron 1 of 2	3
KAZALD1	ENST00000477979.5 link	n.112+688A>T		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.00913

AC:

1390

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00211

AC:

433

AN:

205554

Hom.:

AF XY:

0.00157

AC XY:

181

AN XY:

115278

show subpopulations

Gnomad AFR exome

AF:

0.0336

Gnomad AMR exome

AF:

0.00151

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000746

Gnomad OTH exome

AF:

0.000970

GnomAD4 exome

AF:

0.000959

AC:

1367

AN:

1425294

Hom.:

Cov.:

AF XY:

0.000821

AC XY:

581

AN XY:

707850

show subpopulations

Gnomad4 AFR exome

AF:

0.0352

Gnomad4 AMR exome

AF:

0.00167

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000478

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000318

Gnomad4 OTH exome

AF:

0.00262

GnomAD4 genome

AF:

0.00921

AC:

1402

AN:

152290

Hom.:

Cov.:

AF XY:

0.00861

AC XY:

641

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0327

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00454

Hom.:

Bravo

AF:

0.0106

ESP6500AA

AF:

0.0259

AC:

104

ESP6500EA

AF:

0.000126

AC:

ExAC

AF:

0.00259

AC:

305

Asia WGS

AF:

0.00260

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 25, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0095

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.18

MetaRNN

Benign

0.0037

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.6

REVEL

Benign

0.042

Sift

Benign

0.083

Sift4G

Uncertain

0.043

Polyphen

0.0090

Vest4

0.14

MVP

0.21

MPC

0.36

ClinPred

0.015

GERP RS

0.93

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over