10-101065003-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_030929.5(KAZALD1):c.*83G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 998,274 control chromosomes in the GnomAD database, including 7,997 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.096 (1002 hom., cov: 33)
  • Exomes 𝑓: 0.12 (6995 hom.)
• Consequence: KAZALD1 NM_030929.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.296

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KAZALD1	NM_030929.5	c.*83G>T		3_prime_UTR_variant	5/5	ENST00000370200.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KAZALD1	ENST00000370200.6	c.*83G>T		3_prime_UTR_variant	5/5	1	NM_030929.5	P1
KAZALD1	ENST00000477979.5	n.654G>T		non_coding_transcript_exon_variant	4/4	3
KAZALD1	ENST00000477267.1	n.453+60G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0959 AC: 14583 AN: 152130 Hom.: 1000 Cov.: 33

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.0969

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.214

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.0932

GnomAD4 exome AF: 0.119 AC: 100436 AN: 846026 Hom.: 6995 Cov.: 11 AF XY: 0.121 AC XY: 53405 AN XY: 439908

Gnomad4 AFR exome AF: 0.0199

Gnomad4 AMR exome AF: 0.115

Gnomad4 ASJ exome AF: 0.0945

Gnomad4 EAS exome AF: 0.00130

Gnomad4 SAS exome AF: 0.175

Gnomad4 FIN exome AF: 0.214

Gnomad4 NFE exome AF: 0.117

Gnomad4 OTH exome AF: 0.107

GnomAD4 genome AF: 0.0958 AC: 14592 AN: 152248 Hom.: 1002 Cov.: 33 AF XY: 0.0999 AC XY: 7436 AN XY: 74434

Gnomad4 AFR AF: 0.0219

Gnomad4 AMR AF: 0.0972

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.185

Gnomad4 FIN AF: 0.214

Gnomad4 NFE AF: 0.123

Gnomad4 OTH AF: 0.0960

Alfa AF: 0.104 Hom.: 958

Bravo AF: 0.0817

Asia WGS AF: 0.131 AC: 455 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.42
Dann	Benign	0.48

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: rs12359843; hg19: chr10-102824760; COSMIC: COSV64630078; COSMIC: COSV64630078;