NM_030929.5:c.764G>C

Variant names:

• chr10-101064592-G-C
• rs807037
• NM_030929.5:c.764G>C

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 40 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: Benign. The variant received -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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KAZALD1	NM_030929.5	MANE Select	c.764G>C	p.Gly255Ala	missense	Exon 4 of 5	NP_112191.2
	KAZALD1	NM_001319303.2		c.350G>C	p.Gly117Ala	missense	Exon 4 of 6	NP_001306232.1
	KAZALD1	NR_135067.2		n.380G>C		non_coding_transcript_exon	Exon 3 of 5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KAZALD1	ENST00000370200.6	TSL:1 MANE Select	c.764G>C	p.Gly255Ala	missense	Exon 4 of 5	ENSP00000359219.6
	KAZALD1	ENST00000477267.1	TSL:5	n.279G>C		non_coding_transcript_exon	Exon 3 of 5
	KAZALD1	ENST00000477979.5	TSL:3	n.420G>C		non_coding_transcript_exon	Exon 3 of 4

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

GnomAD2 exomes AF: 0.621 AC: 155693 AN: 250548 AF XY: 0.627

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 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

African (AFR) AF: 0.628 AC: 21020 AN: 33474

American (AMR) AF: 0.547 AC: 24450 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.701 AC: 18318 AN: 26136

East Asian (EAS) AF: 0.424 AC: 16815 AN: 39698

South Asian (SAS) AF: 0.631 AC: 54448 AN: 86246

European-Finnish (FIN) AF: 0.633 AC: 33725 AN: 53276

Middle Eastern (MID) AF: 0.621 AC: 3535 AN: 5696

European-Non Finnish (NFE) AF: 0.665 AC: 739471 AN: 1111938

Other (OTH) AF: 0.650 AC: 39230 AN: 60382

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

African (AFR) AF: 0.629 AC: 26125 AN: 41522

American (AMR) AF: 0.584 AC: 8932 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.692 AC: 2400 AN: 3466

East Asian (EAS) AF: 0.449 AC: 2322 AN: 5172

South Asian (SAS) AF: 0.632 AC: 3048 AN: 4822

European-Finnish (FIN) AF: 0.627 AC: 6634 AN: 10576

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.665 AC: 45173 AN: 67974

Other (OTH) AF: 0.626 AC: 1323 AN: 2112

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 v4.9

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
PhyloP100		6.2
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
Mutation Taster		=93/7	polymorphism (auto)

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