10-101064595-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_030929.5(KAZALD1):c.767G>A(p.Arg256His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,613,936 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0079 (21 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (15 hom.)
• Consequence: KAZALD1 NM_030929.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.17

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011522502).
• BP6: Variant 10-101064595-G-A is Benign according to our data. Variant chr10-101064595-G-A is described in ClinVar as [Benign]. Clinvar id is 773539.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00794 (1209/152330) while in subpopulation AFR AF= 0.0259 (1075/41572). AF 95% confidence interval is 0.0246. There are 21 homozygotes in gnomad4. There are 561 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KAZALD1	NM_030929.5	c.767G>A	p.Arg256His	missense_variant	4/5	ENST00000370200.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KAZALD1	ENST00000370200.6	c.767G>A	p.Arg256His	missense_variant	4/5	1	NM_030929.5	P1
KAZALD1	ENST00000477267.1	n.282G>A		non_coding_transcript_exon_variant	3/5	5
KAZALD1	ENST00000477979.5	n.423G>A		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes AF: 0.00792 AC: 1205 AN: 152212 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.0258

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00237 AC: 593 AN: 250660 Hom.: 7 AF XY: 0.00199 AC XY: 270 AN XY: 135496

Gnomad AFR exome AF: 0.0273

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000539

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00119 AC: 1745 AN: 1461606 Hom.: 15 Cov.: 33 AF XY: 0.00113 AC XY: 819 AN XY: 727090

Gnomad4 AFR exome AF: 0.0276

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.000467

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.00794 AC: 1209 AN: 152330 Hom.: 21 Cov.: 33 AF XY: 0.00753 AC XY: 561 AN XY: 74492

Gnomad4 AFR AF: 0.0259

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00325 Hom.: 4

Bravo AF: 0.00886

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0256 AC: 113

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00283 AC: 344

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 25, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.0073	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.99	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.17
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.044	D
Polyphen		1.0	D
Vest4		0.21
MVP		0.78
MPC		0.67
ClinPred		0.016	T
GERP RS		5.5
Varity_R		0.32
gMVP		0.58

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: rs36116329; hg19: chr10-102824352; COSMIC: COSV99058675; COSMIC: COSV99058675;