10-101064535-G-C

Variant names:

• chr10-101064535-G-C
• rs11190812
• NM_030929.5:c.707G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G236D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• 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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30154026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KAZALD1	NM_030929.5	c.707G>C	p.Gly236Ala	missense_variant	Exon 4 of 5	ENST00000370200.6	NP_112191.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KAZALD1	ENST00000370200.6	c.707G>C	p.Gly236Ala	missense_variant	Exon 4 of 5	1	NM_030929.5	ENSP00000359219.6
KAZALD1	ENST00000477267.1	n.222G>C		non_coding_transcript_exon_variant	Exon 3 of 5	5
KAZALD1	ENST00000477979.5	n.363G>C		non_coding_transcript_exon_variant	Exon 3 of 4	3
KAZALD1	ENST00000470106.1	n.*190G>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.052	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.6	L
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.27
Sift	Benign	0.089	T
Sift4G	Uncertain	0.039	D
Polyphen		0.72	P
Vest4		0.24
MutPred		0.62		Gain of catalytic residue at G236 (P = 0.0168);
MVP		0.75
MPC		0.79
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.38
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs11190812; hg19: chr10-102824292;