10-101063052-G-C

Variant names:

• chr10-101063052-G-C
• rs780548282
• NM_030929.5:c.460G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030929.5(KAZALD1):​c.460G>C​(p.Ala154Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000349 in 1,430,828 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: KAZALD1 NM_030929.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.29

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KAZALD1	NM_030929.5	c.460G>C	p.Ala154Pro	missense_variant	Exon 2 of 5	ENST00000370200.6	NP_112191.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KAZALD1	ENST00000370200.6	c.460G>C	p.Ala154Pro	missense_variant	Exon 2 of 5	1	NM_030929.5	ENSP00000359219.6
KAZALD1	ENST00000470106.1	n.110G>C		non_coding_transcript_exon_variant	Exon 2 of 3	3
KAZALD1	ENST00000477979.5	n.112+937G>C		intron_variant	Intron 1 of 3	3
KAZALD1	ENST00000477267.1	n.-26G>C		upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000898 AC: 2 AN: 222718 Hom.: 0 AF XY: 0.00000808 AC XY: 1 AN XY: 123780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000349 AC: 5 AN: 1430828 Hom.: 0 Cov.: 33 AF XY: 0.00000423 AC XY: 3 AN XY: 709574

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000363

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.37
Sift	Benign	0.099	T
Sift4G	Benign	0.16	T
Polyphen		0.97	D
Vest4		0.28
MutPred		0.48		Gain of glycosylation at A154 (P = 0.0436);
MVP		0.77
MPC		1.2
ClinPred		0.70	D
GERP RS		4.0
Varity_R		0.36
gMVP		0.69

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

Other links and lift over

dbSNP: rs780548282; hg19: chr10-102822809;