10-101062675-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030929.5(KAZALD1):c.83C>T(p.Thr28Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KAZALD1 NM_030929.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.599

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.073934406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KAZALD1	NM_030929.5	c.83C>T	p.Thr28Ile	missense_variant	2/5	ENST00000370200.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KAZALD1	ENST00000370200.6	c.83C>T	p.Thr28Ile	missense_variant	2/5	1	NM_030929.5	P1
KAZALD1	ENST00000470106.1	n.44-311C>T		intron_variant, non_coding_transcript_variant		3
KAZALD1	ENST00000477979.5	n.112+560C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1395358 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 690706

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2021

The c.83C>T (p.T28I) alteration is located in exon 2 (coding exon 1) of the KAZALD1 gene. This alteration results from a C to T substitution at nucleotide position 83, causing the threonine (T) at amino acid position 28 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	13
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.11
Sift	Benign	0.25	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.20		Loss of relative solvent accessibility (P = 0.008);
MVP		0.65
MPC		0.37
ClinPred		0.095	T
GERP RS		1.9
Varity_R		0.045
gMVP		0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-102822432;