rs2295715

Positions:

• chr10-101067471-G-A

Variant summary

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

The ENST00000465807.1(KAZALD1):​n.474G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 368,266 control chromosomes in the GnomAD database, including 6,595 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 0.21 (3628 hom., cov: 33)
  • Exomes 𝑓: 0.16 (2967 hom.)
• Consequence: KAZALD1 ENST00000465807.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.22

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KAZALD1	NM_001319303.2	c.*247G>A		3_prime_UTR_variant	6/6
KAZALD1	XM_017016715.3	c.*224G>A		3_prime_UTR_variant	6/6
KAZALD1	XM_024448213.2	c.*247G>A		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KAZALD1	ENST00000465807.1	n.474G>A		non_coding_transcript_exon_variant	2/2	1
	ENST00000686265.1	n.200C>T		non_coding_transcript_exon_variant	1/1
KAZALD1	ENST00000477267.1	n.677G>A		non_coding_transcript_exon_variant	5/5	5

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31310 AN: 152090 Hom.: 3621 Cov.: 33

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.0842

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.217

GnomAD4 exome AF: 0.157 AC: 33834 AN: 216058 Hom.: 2967 Cov.: 0 AF XY: 0.148 AC XY: 17747 AN XY: 119918

Gnomad4 AFR exome AF: 0.288

Gnomad4 AMR exome AF: 0.238

Gnomad4 ASJ exome AF: 0.138

Gnomad4 EAS exome AF: 0.224

Gnomad4 SAS exome AF: 0.0917

Gnomad4 FIN exome AF: 0.142

Gnomad4 NFE exome AF: 0.162

Gnomad4 OTH exome AF: 0.164

GnomAD4 genome AF: 0.206 AC: 31342 AN: 152208 Hom.: 3628 Cov.: 33 AF XY: 0.203 AC XY: 15109 AN XY: 74414

Gnomad4 AFR AF: 0.298

Gnomad4 AMR AF: 0.238

Gnomad4 ASJ AF: 0.140

Gnomad4 EAS AF: 0.230

Gnomad4 SAS AF: 0.0847

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.164

Gnomad4 OTH AF: 0.216

Alfa AF: 0.174 Hom.: 2872

Bravo AF: 0.221

Asia WGS AF: 0.151 AC: 524 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.17
DANN	Benign	0.90

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2295715; hg19: chr10-102827228;