NM_030929.5:c.460G>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A154T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: KAZALD1 NM_030929.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.29
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030929.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KAZALD1	NM_030929.5	MANE Select	c.460G>C	p.Ala154Pro	missense	Exon 2 of 5	NP_112191.2
	KAZALD1	NM_001319303.2		c.-10G>C		5_prime_UTR	Exon 2 of 6	NP_001306232.1
	KAZALD1	NR_135067.2		n.127+937G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KAZALD1	ENST00000370200.6	TSL:1 MANE Select	c.460G>C	p.Ala154Pro	missense	Exon 2 of 5	ENSP00000359219.6	Q96I82-1
	KAZALD1	ENST00000891380.1		c.460G>C	p.Ala154Pro	missense	Exon 2 of 6	ENSP00000561439.1
	KAZALD1	ENST00000952668.1		c.460G>C	p.Ala154Pro	missense	Exon 1 of 4	ENSP00000622727.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000898 AC: 2 AN: 222718 AF XY: 0.00000808

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 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

African (AFR) AF: 0.00 AC: 0 AN: 32552

American (AMR) AF: 0.00 AC: 0 AN: 43844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25624

East Asian (EAS) AF: 0.00 AC: 0 AN: 38898

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00000363 AC: 4 AN: 1100536

Other (OTH) AF: 0.00 AC: 0 AN: 59376

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.3
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
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs780548282; hg19: chr10-102822809;