rs807037

chr10-101064592-G-Cchr10-101064592-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.764G>C(p.Gly255Ala) variant causes a missense change. The variant allele was found at a frequency of 0.649 in 1,613,692 control chromosomes in the GnomAD database, including 342,283 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.64 (30979 hom., cov: 34)
  • Exomes 𝑓: 0.65 (311304 hom.)
• Consequence: KAZALD1 NM_030929.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.18

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 (MetaRNN=4.402562E-5).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KAZALD1	NM_030929.5	c.764G>C	p.Gly255Ala	missense_variant	4/5	ENST00000370200.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KAZALD1	ENST00000370200.6	c.764G>C	p.Gly255Ala	missense_variant	4/5	1	NM_030929.5	P1
KAZALD1	ENST00000477267.1	n.279G>C		non_coding_transcript_exon_variant	3/5	5
KAZALD1	ENST00000477979.5	n.420G>C		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes AF: 0.636 AC: 96654 AN: 152020 Hom.: 30948 Cov.: 34

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.585

Gnomad ASJ AF: 0.692

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.635

Gnomad FIN AF: 0.627

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.665

Gnomad OTH AF: 0.624

GnomAD3 exomes AF: 0.621 AC: 155693 AN: 250548 Hom.: 49149 AF XY: 0.627 AC XY: 84925 AN XY: 135412

Gnomad AFR exome AF: 0.627

Gnomad AMR exome AF: 0.544

Gnomad ASJ exome AF: 0.699

Gnomad EAS exome AF: 0.430

Gnomad SAS exome AF: 0.634

Gnomad FIN exome AF: 0.625

Gnomad NFE exome AF: 0.664

Gnomad OTH exome AF: 0.631

GnomAD4 exome AF: 0.651 AC: 951012 AN: 1461554 Hom.: 311304 Cov.: 67 AF XY: 0.651 AC XY: 473262 AN XY: 727078

Gnomad4 AFR exome AF: 0.628

Gnomad4 AMR exome AF: 0.547

Gnomad4 ASJ exome AF: 0.701

Gnomad4 EAS exome AF: 0.424

Gnomad4 SAS exome AF: 0.631

Gnomad4 FIN exome AF: 0.633

Gnomad4 NFE exome AF: 0.665

Gnomad4 OTH exome AF: 0.650

GnomAD4 genome AF: 0.636 AC: 96734 AN: 152138 Hom.: 30979 Cov.: 34 AF XY: 0.632 AC XY: 46998 AN XY: 74378

Gnomad4 AFR AF: 0.629

Gnomad4 AMR AF: 0.584

Gnomad4 ASJ AF: 0.692

Gnomad4 EAS AF: 0.449

Gnomad4 SAS AF: 0.632

Gnomad4 FIN AF: 0.627

Gnomad4 NFE AF: 0.665

Gnomad4 OTH AF: 0.626

Alfa AF: 0.659 Hom.: 25043

Bravo AF: 0.630

TwinsUK AF: 0.662 AC: 2455

ALSPAC AF: 0.663 AC: 2555

ESP6500AA AF: 0.631 AC: 2781

ESP6500EA AF: 0.662 AC: 5697

ExAC AF: 0.626 AC: 75997

Asia WGS AF: 0.589 AC: 2047 AN: 3478

EpiCase AF: 0.666

EpiControl AF: 0.663

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.033
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	17
Dann	Benign	0.27
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.000044	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-2.0	N
MutationTaster	Benign	0.99	P
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	3.0	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.081
MPC		0.37
ClinPred		0.0049	T
GERP RS		5.5
Varity_R		0.13
gMVP		0.66

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: rs807037; hg19: chr10-102824349; COSMIC: COSV64629991; COSMIC: COSV64629991;