10-101062803-A-T

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.211A>T(p.Arg71Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,577,584 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0092 (20 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (33 hom.)
• Consequence: KAZALD1 NM_030929.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.252

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=0.0037122667).
• BP6: Variant 10-101062803-A-T is Benign according to our data. Variant chr10-101062803-A-T is described in ClinVar as [Benign]. Clinvar id is 716217.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00921 (1402/152290) while in subpopulation AFR AF= 0.0327 (1358/41564). AF 95% confidence interval is 0.0312. There are 20 homozygotes in gnomad4. There are 641 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KAZALD1	NM_030929.5	c.211A>T	p.Arg71Trp	missense_variant	2/5	ENST00000370200.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KAZALD1	ENST00000370200.6	c.211A>T	p.Arg71Trp	missense_variant	2/5	1	NM_030929.5	P1
KAZALD1	ENST00000470106.1	n.44-183A>T		intron_variant, non_coding_transcript_variant		3
KAZALD1	ENST00000477979.5	n.112+688A>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00913 AC: 1390 AN: 152172 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

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: 0.0000588

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00211 AC: 433 AN: 205554 Hom.: 5 AF XY: 0.00157 AC XY: 181 AN XY: 115278

Gnomad AFR exome AF: 0.0336

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000746

Gnomad OTH exome AF: 0.000970

GnomAD4 exome AF: 0.000959 AC: 1367 AN: 1425294 Hom.: 33 Cov.: 33 AF XY: 0.000821 AC XY: 581 AN XY: 707850

Gnomad4 AFR exome AF: 0.0352

Gnomad4 AMR exome AF: 0.00167

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000478

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000318

Gnomad4 OTH exome AF: 0.00262

GnomAD4 genome AF: 0.00921 AC: 1402 AN: 152290 Hom.: 20 Cov.: 33 AF XY: 0.00861 AC XY: 641 AN XY: 74474

Gnomad4 AFR AF: 0.0327

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00454 Hom.: 0

Bravo AF: 0.0106

ESP6500AA AF: 0.0259 AC: 104

ESP6500EA AF: 0.000126 AC: 1

ExAC AF: 0.00259 AC: 305

Asia WGS AF: 0.00260 AC: 9 AN: 3476

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0095	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.042
Sift	Benign	0.083	T
Sift4G	Uncertain	0.043	D
Polyphen		0.0090	B
Vest4		0.14
MVP		0.21
MPC		0.36
ClinPred		0.015	T
GERP RS		0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
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: rs61731071; hg19: chr10-102822560;