Genetic Variant NM_030929.5:c.707G>C (chr10-101064535-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_030929.5(KAZALD1):c.707G>C(p.Gly236Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30154026).

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>C	p.Gly236Ala	missense	Exon 4 of 5	NP_112191.2
KAZALD1	NM_001319303.2		c.293G>C	p.Gly98Ala	missense	Exon 4 of 6	NP_001306232.1
KAZALD1	NR_135067.2		n.323G>C		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>C	p.Gly236Ala	missense	Exon 4 of 5	ENSP00000359219.6
KAZALD1	ENST00000477267.1	TSL:5	n.222G>C		non_coding_transcript_exon	Exon 3 of 5
KAZALD1	ENST00000477979.5	TSL:3	n.363G>C		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

547

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.052

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.024

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.6

PhyloP100

5.7

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.27

Sift

Benign

0.089

Sift4G

Uncertain

0.039

Polyphen

0.72

Vest4

0.24

MutPred

0.62

Gain of catalytic residue at G236 (P = 0.0168)

MVP

0.75

MPC

0.79

ClinPred

0.98

GERP RS

5.6

Varity_R

0.38

gMVP

0.59

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over