10-101062679-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_030929.5(KAZALD1):c.87C>T(p.Gly29=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,544,824 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (39 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (52 hom.)
• Consequence: KAZALD1 NM_030929.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.517

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 10-101062679-C-T is Benign according to our data. Variant chr10-101062679-C-T is described in ClinVar as [Benign]. Clinvar id is 781215.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.517 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0138 (2105/152358) while in subpopulation AFR AF= 0.0474 (1973/41592). AF 95% confidence interval is 0.0457. There are 39 homozygotes in gnomad4. There are 988 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KAZALD1	NM_030929.5	c.87C>T	p.Gly29=	synonymous_variant	2/5	ENST00000370200.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KAZALD1	ENST00000370200.6	c.87C>T	p.Gly29=	synonymous_variant	2/5	1	NM_030929.5	P1
KAZALD1	ENST00000470106.1	n.44-307C>T		intron_variant, non_coding_transcript_variant		3
KAZALD1	ENST00000477979.5	n.112+564C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2098 AN: 152240 Hom.: 39 Cov.: 33

Gnomad AFR AF: 0.0474

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00337 AC: 484 AN: 143712 Hom.: 13 AF XY: 0.00227 AC XY: 181 AN XY: 79814

Gnomad AFR exome AF: 0.0561

Gnomad AMR exome AF: 0.00347

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000827

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000275

Gnomad OTH exome AF: 0.00142

GnomAD4 exome AF: 0.00152 AC: 2112 AN: 1392466 Hom.: 52 Cov.: 32 AF XY: 0.00134 AC XY: 921 AN XY: 689014

Gnomad4 AFR exome AF: 0.0464

Gnomad4 AMR exome AF: 0.00387

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000123

Gnomad4 FIN exome AF: 0.0000866

Gnomad4 NFE exome AF: 0.000251

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.0138 AC: 2105 AN: 152358 Hom.: 39 Cov.: 33 AF XY: 0.0133 AC XY: 988 AN XY: 74502

Gnomad4 AFR AF: 0.0474

Gnomad4 AMR AF: 0.00542

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00623 Hom.: 4

Bravo AF: 0.0160

Asia WGS AF: 0.00173 AC: 6 AN: 3478

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

Jul 16, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	12
Dann	Benign	0.92

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: rs7906652; hg19: chr10-102822436;